Organic compounds

ABSTRACT

The invention relates to particular substituted heterocycle fused gamma-carbolines, their prodrugs, in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving the 5-HT2A receptor, the serotonin transporter (SERT), pathways involving the dopamine D1 and D2 receptor signaling system, and/or the μ-opioid receptor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Stage application under 35 U.S.C. § 371 of International Application No. PCT/US2018/043100, filed on Jul. 20, 2018, which claims priority to and the benefit of U.S. Provisional Application Nos. 62/537,287, filed on Jul. 26, 2017; 62/639,244 filed on Mar. 6, 2018; and 62/682,546, filed on Jun. 8, 2018; the contents of each of which are hereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The invention relates to new methods and uses pertaining to particular substituted heterocycle fused gamma-carbolines, their prodrugs, in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, and pharmaceutical compositions thereof, such as methods of use in the treatment of diseases involving the 5-HT_(2A) receptor, the serotonin transporter (SERT), pathways involving dopamine D₁ and D₂ receptor signaling systems, and/or the μ-opioid receptor, e.g., diseases or disorders such as anxiety, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility and obesity; depression and mood disorders associated with psychosis or Parkinson's disease; psychosis such as schizophrenia associated with depression; bipolar disorder; mood disorders; drug dependencies, such as opiate dependency and alcohol dependency, drug withdrawal symptoms, and other psychiatric and neurological conditions, as well as to combinations with other agents. In addition, such compounds and compositions are useful in methods of treatment of obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), and related disorders. In some embodiments, the disease or disorders may include treatment-resistant depression, cocaine dependency, and/or amphetamine dependency, opioid use disorder and the symptoms of opioid withdrawal.

BACKGROUND OF THE INVENTION

Substituted heterocycle fused gamma-carbolines are known to be agonists or antagonists of 5-HT₂ receptors, particularly 5-HT_(2A) and 5-HT_(2C) receptors, in treating central nervous system disorders. These compounds have been disclosed in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; U.S. RE39680, and U.S. RE39679, as novel compounds useful for the treatment of disorders associated with 5-HT_(2A) receptor modulation such as obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders migraine, conditions associated with cephalic pain, social phobias, gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility, and obesity. PCT/US08/03340 (WO 2008/112280), and its U.S. equivalent US 2010/113781, and U.S. application Ser. No. 10/786,935 (published as US 2004/209864) also disclose methods of making substituted heterocycle fused gamma-carbolines and uses of these gamma-carbolines as serotonin agonists and antagonists useful for the control and prevention of central nervous system disorders such as addictive behavior and sleep disorders.

In addition, WO/2009/145900 (and its equivalent US 2011/071080) discloses use of particular substituted heterocycle fused gamma-carbolines for the treatment of a combination of psychosis and depressive disorders as well as sleep, depressive and/or mood disorders in patients with psychosis or Parkinson's disease. In addition to disorders associated with psychosis and/or depression, this patent application discloses and claims use of these compounds at a low dose to selectively antagonize 5-HT_(2A) receptors without affecting or minimally affecting dopamine D₂ receptors, thereby useful for the treatment of sleep disorders without the side effects associated with high occupancy of the dopamine D₂ pathways or side effects of other pathways (e.g., GABA_(A) receptors) associated with convention sedative-hypnotic agents (e.g., benzodiazepines) including but not limited to the development of drug dependency, muscle hypotonia, weakness, headache, blurred vision, vertigo, nausea, vomiting, epigastric distress, diarrhea, joint pains, and chest pains. WO 2009/114181 (and its equivalent US 2011/112105) also discloses of methods of preparing toluenesulfonic acid addition salt crystals of these substituted heterocycle fused gamma-carbolines.

In addition, recent evidence shows that the aforementioned substituted fused heterocycle gamma carbolines may operate, in part, through NMDA receptor antagonism via mTOR1 signaling, in a manner similar to that of ketamine. Ketamine is a selective NMDA receptor antagonist. Ketamine acts through a system that is unrelated to the common psychogenic monoamines (serotonin, norepinephrine and dopamine), and this is a major reason for its much more rapid effects. Ketamine directly antagonizes extrasynaptic glutamatergic NMDA receptors, which also indirectly results in activation of AMPA-type glutamate receptors. The downstream effects involve the brain-derived neurotrophic factor (BDNF) and mTORC1 kinase pathways. Similar to ketamine, recent evidence suggests that compounds related to those of the present disclosure enhance both NMDA and AMPA-induced currents in rat medial prefrontal cortex pyramidal neurons via activation of D1 receptors, and that this is associated with increased mTORC1 signaling.

Metabolites of compounds disclosed in the aforementioned publications, as well as related compounds, are also disclosed in WO 2017/132408 and US 2017/319580.

Obsessive-compulsive disorder (OCD) and related disorders, have become highly prevalent and are difficult to treat. OCD is estimated to affect about 2.3% of people at some point in their lives, and during a given year, it is estimated than 1.2% of people worldwide suffer from the disorder. Half of people who suffer from OCD begin to show symptoms before the age of 20, which can seriously affect their ability to obtain an adequate and effective education. Without effective treatment, however, the disease can last for decades. The mainstay of pharmacologic OCD treatment is with selective serotonin reuptake inhibitors (SSRIs). A second line of therapy is with antipsychotic agents, such as clomipramine, risperidone, quetiapine and olanzapine. A significant number of patients either do not respond to these agents, or cannot handle the side effects caused by these agents. More recently, it has been reported that the opioid analgesic tramadol may be effective in treating OCD. Opiates operate by an entirely different pathway from traditional OCD treatment agents, so they offer the possibility of treatment for people who cannot take the traditional serotonergic agents or for whom these agents are ineffective. However, strong opiate agents can be addictive, and their use may be contraindicated in some patients. There thus remains an urgent need for new treatments for pain, OCD and other disorders.

Drug dependency disorders, such as opiate use disorder (OUD), are another group of disorders which are difficult to successfully treat. Opioid overdoses claim approximately 100 lives in the United States every day, and the opioid epidemic continues to grow in the United States. Methadone, buprenorphine, and naltrexone are the most frequently used treatments for OUD. Methadone is a mu-opioid receptor (MOP) agonist, buprenorphine is an MOP partial agonist, and naltrexone is an MOP antagonist. Each of these agents has had limited success, and long-term adherence to prescribed therapies for OUD remains low. In addition, these treatments often exacerbate common co-morbidities associated with OUD, such as mood and anxiety disorders, which further increases the risk of remission. Abrupt opioid abuse withdrawal (i.e., going “cold turkey”) is also associated with severe side effects, including dysphoria, depression and anxiety, and the common treatment agents do not address these problems, and may make them worse. There is thus an urgent need for improved OUD treatments.

SUMMARY OF THE INVENTION

The compounds of the present disclosure have been unexpectedly found to have potent activity at serotonin receptors (e.g., 5-HT_(2A)), serotonin transporters (SERT), dopamine receptors (e.g., D1 and/or D2), and Mu-opiate receptor, and they further display the unique Mu-opiate receptor activity of a biased ligand. It is also believed that the compounds of the present disclosure, via their D1 receptor activity, may also enhance NMDA and AMPA mediated signaling through the mTOR pathway.

The present disclosure provides Compounds of Formula I that are useful for the treatment or prophylaxis of central nervous system disorders. In a first aspect, the present disclosure relates to a compound (Compound I) of Formula I:

wherein:

-   -   X is —NH— or —N(CH₃)—;     -   L is selected from O, NH, NR^(a), and S;     -   Z is —CH(O—R₁)—, —O— or —C(═O)—;     -   R₁ is H, —C(O)—C₁₋₂₁ alkyl (e.g., —C(O)—C₁₋₅ alkyl, —C(O)—C₆₋₁₅         alkyl or —C(O)—C₁₆₋₂₁ alkyl), preferably said alkyl is a         straight chain, optionally saturated or unsaturated and         optionally substituted with one or more hydroxy or C₁-22 alkoxy         (e.g., ethoxy) groups, for example R₁ is C(O)—C₃ alkyl, —C(O)C₆         alkyl, —C(O)—C₇ alkyl, —C(O)—C₉ alkyl, —C(O)—C₁₁ alkyl,         —C(O)—C₁₃ alkyl or —C(O)—C₁₅ alkyl;     -   R^(a) is:         -   halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, or C₃₋₆             cycloalkyl, each of which can be independently substituted             with up to three independently selected R^(b) groups, for             example C-₁₋₃ haloalkyl or C₁₋₃ hydroxyalkyl; or         -   aryl optionally substituted with up to five independently             selected R^(b); and each R^(b) is independently selected             from H, halogen, NH₂, NO₂, OH, C(O)OH, CN, SO₃, and C₁₋₄             alkyl;

in free or salt form, for example in an isolated or purified free or salt form.

The present disclosure provides additional exemplary embodiments of the Compound of Formula I, in free or salt form, for example in an isolated or purified free or salt form, including:

-   -   1.1 Compound I, wherein L is —O—;     -   1.2 Compound I or 1.1, wherein Z is —CH(O—R₁)—;     -   1.3 Compound I or 1.1, wherein Z is —C(═O)—;     -   1.4 Compound I, wherein L is NH.     -   1.5 Compound I, wherein L is NR^(a);     -   1.6 Compound I, wherein L is S;     -   1.7 Compound I or any of 1.1-1.6, in solid form, for example in         solid salt form;     -   1.8 Compound I or any of 1.1-1.7, wherein Z is —CH(O—R₁)—;     -   1.9 Compound I, or any of 1.1-1.7, wherein Z is —C(═O)—;     -   1.10 Compound I, or any of 1.1-1.7, wherein Z is —O—;     -   1.11 Compound I or any of 1.1-1.10, wherein X is —NH—;     -   1.12 Compound I or any of 1.1-1.10, wherein X is —N(CH₃)—;     -   1.13 Compound I or any of 1.1-1.12, wherein L is —O— and X is         —N(CH₃)—;     -   1.14 Compound I or any of 1.1-1.12, wherein L is —O— and X is         —NH—;     -   1.15 Compound 1.13, wherein Z is —C(═O)—;     -   1.16 Compound 1.14, wherein Z is —C(═O)—;     -   1.17 Compound I or any of 1.1-1.14, wherein Z is —CH(O—R₁)— and         R₁ is H;     -   1.18 Compound I or any of 1.1-1.14, wherein Z is —CH(O—R₁)— and         R₁ is —C(O)—C₁₋₅ alkyl, —C(O)—C₆₋₁₅ alkyl or —C(O)—C₁₆₋₂₁ alkyl;     -   1.19 Compound I or any of 1.1-1.14, wherein Z is —CH(O—R₁)— and         R₁ is selected from the group consisting of C(O)—C₃ alkyl,         —C(O)C₆ alkyl, —C(O)—C₇ alkyl, —C(O)—C₉ alkyl, —C(O)—C₁₁ alkyl,         —C(O)—C₁₃ alkyl or —C(O)—C₁₅ alkyl; for example, wherein R¹ is         acetyl, ethylcarbonyl, or propylcarbonyl;     -   1.20 Compound I or any of 1.1-1.12 or 1.17-1.19, wherein L is         NR^(a), and wherein R^(a) is: halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl,         C₂₋₄ alkynyl, or C₃₋₆ cycloalkyl, each of which can be         independently substituted with up to three independently         selected R^(b) groups; or wherein R^(a) is aryl optionally         substituted with up to five independently selected R^(b);         wherein R^(b) is independently selected from H, halogen, NH₂,         NO₂, OH, C(O)OH, CN, SO₃, and C₁₋₄ alkyl;     -   1.21 Compound 1.20, wherein R^(a) is C₁₋₄ alkyl or C₃₋₆         cycloalkyl, optionally substituted with up to three         independently selected R^(b) groups;     -   1.22 Compound 1.20, wherein R^(a) is aryl, optionally         substituted with up to three independently selected R^(b)         groups;     -   1.23 Compound 1.20, wherein R^(a) is selected from the group         consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl,         sec-butyl, or phenyl;     -   1.24 Compound I, or any of 1.1-1.14 or 1.17-1.23, wherein Z is         —CH(O—R₁)—; and said carbon atom CH in the group —CH(O—R₁)— has         either the R configuration or the S configuration, or a mixture         thereof;     -   1.25 Compound 1.24, wherein the carbon atom CH is substantially         present in either the R configuration or the S configuration,         e.g., wherein the diastereomer having the R configuration or the         S configuration at this carbon is present in greater than 70%         diastereomeric excess, for example, greater than 75%, or greater         than 80%, or greater than 85%, or greater than 90%, or greater         than 95%, or greater than 97%, or greater than 98% or greater         than 99%, diastereomeric excess.     -   1.26 Compound I, or any of 1.1-1.25, wherein the compound is         selected from the group consisting of:

-   -   1.27 Compound I, or any of 1.1-1.25, wherein the compound is         selected from the group consisting of:

-   -   1.28 Compound I, or any of 1.1-1.27, wherein the compound is

in free or salt form (e.g., pharmaceutically acceptable salt form);

-   -   1.29 Compound I, or any of 1.1-1.27, wherein the compound is

-   -   1.30         in free or salt form (e.g., pharmaceutically acceptable salt         form);     -   1.31 Compound I, or any of 1.1-1.27, wherein the compound is

-   -   1.32         in free or salt form (e.g., pharmaceutically acceptable salt         form);     -   1.33 Compound I, or any of 1.1-1.32, in free form;     -   1.34 Compound I, or any of 1.1-1.32 in salt form, e.g.,         pharmaceutically acceptable salt form;     -   1.35 Compound I or any of 1.1-1.34 in solid form.

in free or salt form, for example in an isolated or purified free or salt form.

In a second aspect, the present disclosure relates to a compound (Compound II) of Formula II:

wherein:

-   -   X is —NH— or —N(CH₃)—;     -   Y is —CH(O—R₁)— or —C(═O)—;     -   R₁ is H, —C(O)—C₁₋₂₁ alkyl (e.g., —C(O)—C₁₋₅ alkyl, —C(O)—C₆₋₁₅         alkyl or —C(O)—C₁₆₋₂₁ alkyl), preferably said alkyl is a         straight chain, optionally saturated or unsaturated and         optionally substituted with one or more hydroxy or C₁₋₂₂ alkoxy         (e.g., ethoxy) groups, for example R₁ is C(O)—C₃ alkyl, —C(O)C₆         alkyl, —C(O)—C₇ alkyl, —C(O)—C₉ alkyl, —C(O)—C₁₁ alkyl,         —C(O)—C₁₃ alkyl or —C(O)—C₁₅ alkyl;

in free or salt form, for example in an isolated or purified free or salt form.

The present disclosure provides additional exemplary embodiments of the Compound of Formula II, in free or salt form, for example in an isolated or purified free or salt form, including:

-   -   2.1 Compound II, wherein X is —NH—;     -   2.2 Compound II, wherein X is —N(CH₃)—;     -   2.3 Compound II, or 2.1-2.4, wherein Y is —C(═O)—;     -   2.4 Compound II, wherein Y is —CH(O—R₁)—; i.e., having the         Formula II-A:

-   -   2.5 Compound II, or 2.1-2.4, wherein Y is —CH(O—R₁)—;     -   2.6 Compound II, wherein X is NH and Y is —C(═O)—; i.e., having         the Formula II-B:

-   -   2.7 Compound II, wherein X is —NH— and Y is —CH(O—R₁)—;     -   2.8 Compound II, wherein X is —NH— and Y is —CH(O—R₁)—, wherein         R₁ is H; i.e., having the Formula II-C:

-   -   2.9 Compound II, wherein X is —N(CH₃)— and Y is —C(═O)—; i.e.,         having the Formula II-D:

-   -   2.10 Compound II, wherein X is —N(CH₃)— and Y is —CH(O—R₁)—;     -   2.11 Compound II, wherein X is —N(CH₃)— and Y is —CH(O—R₁)—,         wherein R₁ is H; i.e., having the Formula II-E:

-   -   2.12 Compound II or any of 2.1-2.11, in solid form, for example         in solid salt form.

In a third aspect, the present disclosure relates to a compound (Compound III) of Formula III:

wherein:

-   -   X is —NH— or —N(CH₃)—;     -   R₁ is H, —C(O)—C₁₋₂₁ alkyl (e.g., —C(O)—C₁₋₅ alkyl, —C(O)—C₆₋₁₅         alkyl or —C(O)—C₁₆₋₂₁ alkyl), preferably said alkyl is a         straight chain, optionally saturated or unsaturated and         optionally substituted with one or more hydroxy or C₁₋₂₂ alkoxy         (e.g., ethoxy) groups, for example R₁ is C(O)—C₃ alkyl, —C(O)C₆         alkyl, —C(O)—C₇ alkyl, —C(O)—C₉ alkyl, —C(O)—C₁₁ alkyl,         —C(O)—C₁₃ alkyl or —C(O)—C₁₅;

in free or salt form, for example in an isolated or purified free or salt form.

The present disclosure provides additional exemplary embodiments of the Compound of Formula III, in free or salt form, for example in an isolated or purified free or salt form. including:

-   -   3.1 Compound III, wherein R₁ is H; i.e., having the Formula         III-A:

-   -   -   in free or salt form, for example in an isolated or purified             free or salt form;

    -   3.2 Compound III or 3.1, wherein X is —NH—;

    -   3.3 Compound III or 3.1, wherein X is —N(CH₃)—;

    -   3.4 Compound 3.1, wherein X is —NH—; i.e., having the Formula         III-B:

-   -   3.5 Compound 3.1, wherein X is —N(CH₃)—; i.e., having the         Formula III-C:

-   -   3.6 Compound III or any of 3.1-3.5, wherein the Compound has a         diastereomeric excess of greater than 70%;     -   3.7 Compound III or any of 3.1-3.6, wherein the Compound has a         diastereomeric excess of greater than 80%;     -   3.8 Compound III or any of 3.1-3.7, wherein the Compound has a         diastereomeric excess of greater than 90%;     -   3.9 Compound III or any of 3.1-3.8, wherein the Compound has a         diastereomeric excess of greater than 95%;     -   3.10 Compound III or any of 3.1-3.9, wherein the Compound is in         substantially pure diastereomeric form (i.e., substantially free         from other diastereomers)     -   3.11 Compound III or any of 3.1-3.10, in solid form, for example         in solid salt form.

In a fourth aspect, the present disclosure relates to a compound (Compound IV) of Formula IV:

wherein:

-   -   X is —NH— or —N(CH₃)—;     -   R₁ is H, —C(O)—C₁₋₂₁ alkyl (e.g., —C(O)—C₁₋₅ alkyl, —C(O)—C₆₋₁₅         alkyl or —C(O)—C₁₆₋₂₁ alkyl), preferably said alkyl is a         straight chain, optionally saturated or unsaturated and         optionally substituted with one or more hydroxy or C₁₋₂₂ alkoxy         (e.g., ethoxy) groups, for example R₁ is C(O)—C₃ alkyl, —C(O)C₆         alkyl, —C(O)—C₇ alkyl, —C(O)—C₉ alkyl, —C(O)—C₁₁ alkyl,         —C(O)—C₁₃ alkyl or —C(O)—C₁₅ alkyl;

in free or salt form, for example in an isolated or purified free or salt form.

The present disclosure provides additional exemplary embodiments of the Compound of Formula IV, in free or salt form, for example in an isolated or purified free or salt form, including:

-   -   4.1 Compound IV, wherein R₁ is H; i.e., having the Formula IV-A:

-   -   -   in free or salt form, for example in an isolated or purified             free or salt form.

    -   4.2 Compound IV or 4.1, wherein X is —NH—;

    -   4.3 Compound IV or 4.1, wherein X is —N(CH₃)—;

    -   4.4 Compound 4.1, wherein X is —NH—; i.e., having the Formula         IV-B:

-   -   4.5 Compound 4.1, wherein X is —N(CH₃)—; i.e., having the         Formula IV-C:

-   -   4.6 Compound IV or any of 4.1-4.5, wherein the Compound has a         diastereomeric excess of greater than 70%     -   4.7 Compound IV or any of 4.1-4.6, wherein the Compound has a         diastereomeric excess of greater than 80%     -   4.8 Compound IV or any of 4.1-4.7, wherein the Compound has a         diastereomeric excess of greater than 90%     -   4.9 Compound IV or any of 4.1-4.8, wherein the Compound has a         diastereomeric excess of greater than 95%     -   4.10 Compound IV or any of 4.1-4.9, wherein the Compound is in         substantially pure diastereomeric form (i.e., substantially free         from other diastereomers);     -   4.11 Compound IV or any of 4.1-4.10, in solid form, for example         in solid salt form.

In a fifth aspect, the present disclosure provides each of the foregoing Compound I or 1.1-1.35, Compound II or 2.1-2.12, Compound III or 3.1-3.11, or Compound IV or 4.1-4.11 (hereinafter collectively “Compounds of Formulas I-IV et seq.” or “compounds of the disclosure”) in free or pharmaceutically acceptable salt form. The present disclosure provides additional exemplary embodiments of the Compounds of Formulas I-IV et seq., including:

-   -   5.1 Compounds of Formulas I-IV et seq., wherein the salt is an         acid addition salt selected from hydrochloric, hydrobromic,         sulfuric, sulfamic, phosphoric, nitric, acetic, propionic,         succinic, glycolic, stearic, lactic, malic, tartaric, citric,         ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,         benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,         toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic,         isethionic, and the like;     -   5.2 Compounds of Formulas I-IV et seq., wherein the salt is         fumaric acid addition salt;     -   5.3 Compounds of Formulas I-IV et seq., wherein the salt is         phosphoric acid addition salt;     -   5.4 Compounds of Formulas I-IV et seq., wherein the salt is a         toluenesulfonic acid addition salt;     -   5.5 Any of 5.1-5.4 wherein the salt is in solid form.

In a sixth aspect, the present disclosure provides a pharmaceutical composition (Pharmaceutical Composition 6) comprising a compound according to any one of Compound I or 1.1-1.35, Compound II or 2.1-2.12, Compound III or 3.1-3.11, or Compound IV or 4.1-4.11 (collectively, Compounds of Formulas I-IV et seq. or compounds of the disclosure), e.g., in admixture with a pharmaceutically acceptable diluent or carrier. The present disclosure provides additional exemplary embodiments of Pharmaceutical Composition 6, including:

-   -   6.1 Pharmaceutical Composition 6, comprising Compound I or any         of 1.1-1.35;     -   6.2 Pharmaceutical Composition 6, comprising Compound II or any         of 2.1-2.12;     -   6.3 Pharmaceutical Composition 6, comprising Compound III or any         of 3.1-3.11;     -   6.4 Pharmaceutical Composition 6, comprising Compound IV or any         of 4.1-4.11;     -   6.5 Pharmaceutical Composition 6 or any of 6.1-6.4, wherein the         Compound of Formula I-IV et seq. is in solid form;     -   6.6 Pharmaceutical Composition 6 or any of 6.1-6.5, wherein the         Compound of Formulas I-IV et seq. is in pharmaceutically         acceptable salt form as described in Compounds 5.1-5.5;     -   6.7 Pharmaceutical Composition 6 or any of 6.1-6.6, wherein the         Compound of Formulas I-IV et seq. is in admixture with a         pharmaceutically acceptable diluent or carrier.

In a preferred embodiment, the Pharmaceutical Composition of the present disclosure comprises a Compound of Formula II-A, II-B, or II-C, in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier. In another preferred embodiment, the Pharmaceutical Composition of the present disclosure comprises a Compound of Formula III-A, III-B or III-C in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier. In another preferred embodiment, the Pharmaceutical Composition of the present disclosure comprises a Compound of Formula IV-A, IV-B or IV-C in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier.

In a further embodiment, the Pharmaceutical Compositions of the present disclosure, are for a sustained or delayed release, e.g., depot, formulation. In one embodiment, the depot formulation (Depot Formulation 6.8) is the Pharmaceutical Composition of any of 6.1-6.7, preferably in free or pharmaceutically acceptable salt form, and preferably in admixture with a pharmaceutically acceptable diluent or carrier, e.g., providing sustained or delayed release as an injectable depot.

In a further embodiment, the Depot Composition (Depot Composition 6.9) comprises Pharmaceutical Composition of any of 6.1-6.7, wherein R₁ is a —C(O)—C₆₋₁₅alkyl, in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier.

In a further embodiment, the present disclosure provides Pharmaceutical Composition 6.10, which is Pharmaceutical Composition 6 or any of 6.1-6.9, wherein the Compound of Formulas I-IV et seq. is in a polymeric matrix. In one embodiment, the Compound of the present disclosure is dispersed or dissolved within the polymeric matrix. In a further embodiment, the polymeric matrix comprises standard polymers used in depot formulations such as polymers selected from a polyester of a hydroxyfatty acid and derivatives thereof, or a polymer of an alkyl alpha-cyanoacrylate, a polyalkylene oxalate, a polyortho ester, a polycarbonate, a polyortho-carbonate, a polyamino acid, a hyaluronic acid ester, and mixtures thereof. In a further embodiment, the polymer is selected from a group consisting of polylactide, poly d,l-lactide, poly glycolide, PLGA 50:50, PLGA 85:15 and PLGA 90:10 polymer. In another embodiment, the polymer is selected form poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes, such as, glycerol mono- and distearate, and the like. In a preferred embodiment, the polymeric matrix comprises poly(d,l-lactide-co-glycolide).

For example, in one embodiment of Pharmaceutical Composition 6.10, the Compound is the Compound of Formula I, wherein X is —NH— or —N(CH₃)— and Y is —C(═O)— or —C(H)(OH)—, in free or pharmaceutically acceptable salt form. In another example of Pharmaceutical Composition 6.10, the Compound is the Compound of Formula II-A, II-B, or II-C, in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier. In another example of Pharmaceutical Composition 6.10, the Compound is the Compound of Formula III-A, III-B or III-C in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier. In another example of Pharmaceutical Composition 6.10, the Compound is the Compound of Formula IV-A, IV-B or IV-C in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier. In another embodiment of each of the foregoing examples of Pharmaceutical Composition 6.10, the polymeric matrix comprises a poly(d,l-lactide-co-glycolide).

The (Pharmaceutical) Compositions 6 and 6.1-6.10 are particularly useful for sustained or delayed release, wherein the Compound of the present disclosure is released upon degradation of the polymeric matrix. These Compositions may be formulated for controlled- and/or sustained-release of the Compounds of the present disclosure (e.g., as a depot composition) over a period of up to 180 days, e.g., from about 14 to about 30 to about 180 days. For example, the polymeric matrix may degrade and release the Compounds of the present disclosure over a period of about 30, about 60 or about 90 days. In another example, the polymeric matrix may degrade and release the Compounds of the present disclosure over a period of about 120, or about 180 days.

In still another embodiment, the Pharmaceutical Compositions of the present disclosure, for example the depot composition of the present disclosure, e.g., Pharmaceutical Composition 6.10, is formulated for administration by injection.

In a seventh aspect, the present disclosure provides the Compounds of Formulas I-IV et seq. as hereinbefore described, in an osmotic controlled release oral delivery system (OROS), which is described in WO 2000/35419 and EP 1 539 115 (U.S. Pub. No. 2009/0202631), the contents of each of which applications are incorporated by reference in their entirety. Therefore in one embodiment of the seventh aspect, the present disclosure provides a pharmaceutical composition or device comprising (a) a gelatin capsule containing a Compound of any of Formulae I-IV et seq. in free or pharmaceutically acceptable salt form or a Pharmaceutical Composition of the Invention, as hereinbefore described; (b) a multilayer wall superposed on the gelatin capsule comprising, in outward order from the capsule: (i) a barrier layer, (ii) an expandable layer, and (iii) a semipermeable layer; and (c) and orifice formed or formable through the wall (Pharmaceutical Composition P.1).

In another embodiment, the invention provides a pharmaceutical composition comprising a gelatin capsule containing a liquid, the Compound of Formulas I-IV et seq. in free or pharmaceutically acceptable salt form or a Pharmaceutical Composition of the Invention, e.g., any of Pharmaceutical Composition 6 or 6.1-6.10, the gelatin capsule being surrounded by a composite wall comprising a barrier layer contacting the external surface of the gelatin capsule, an expandable layer contacting the barrier layer, a semi-permeable layer encompassing the expandable layer, and an exit orifice formed or formable in the wall (Pharmaceutical Composition P.2).

In still another embodiment of the seventh aspect, the invention provides a composition comprising a gelatin capsule containing a liquid, the Compound of Formulas I-IV et seq. in free or pharmaceutically acceptable salt form or a Pharmaceutical Composition of the Invention, e.g., any of Pharmaceutical Composition 6 or 6.1-6.10, the gelatin capsule being surrounded by a composite wall comprising a barrier layer contacting the external surface of the gelatin capsule, an expandable layer contacting the barrier layer, a semipermeable layer encompassing the expandable layer, and an exit orifice formed or formable in the wall, wherein the barrier layer forms a seal between the expandable layer and the environment at the exit orifice (Pharmaceutical Composition P.3).

In still another embodiment of the seventh aspect, the invention provides a composition comprising a gelatin capsule containing a liquid, the Compound of Formulas I-IV et seq. in free or pharmaceutically acceptable salt form or a Pharmaceutical Composition of the Invention, e.g., any of Pharmaceutical Composition 6 or 6.1-6.10, the gelatin capsule being surrounded by a barrier layer contacting the external surface of the gelatin capsule, an expandable layer contacting a portion of the barrier layer, a semi-permeable layer encompassing at least the expandable layer, and an exit orifice formed or formable in the dosage form extending from the external surface of the gelatin capsule to the environment of use (Pharmaceutical Composition P.4). The expandable layer may be formed in one or more discrete sections, such as for example, two sections located on opposing sides or ends of the gelatin capsule.

In a particular embodiment of the seventh aspect, the Compound of the present disclosure in the Osmotic-controlled Release Oral Delivery System (i.e., in Pharmaceutical Composition P.1-P.4) is in a liquid formulation, which formulation may be neat, liquid active agent, liquid active agent in a solution, suspension, emulsion or self-emulsifying composition or the like.

Further information on Osmotic-controlled Release Oral Delivery System composition including characteristics of the gelatin capsule, barrier layer, an expandable layer, a semi-permeable layer; and orifice may be found in WO 2000/35419 and US 2001/0036472, the contents of which are incorporated by reference in their entirety.

Other Osmotic-controlled Release Oral Delivery System for the Compound of Formulas I-IV et seq. or the Pharmaceutical Composition of the present disclosure may be found in EP 1 539 115 (U.S. Pub. No. 2009/0202631), the contents of which are incorporated by reference in their entirety. Therefore, in another embodiment of the seventh aspect, the invention provides a composition or device comprising (a) two or more layers, said two or more layers comprising a first layer and a second layer, said first layer comprises the Compound of Formulas I-IV et seq., in free or pharmaceutically acceptable salt form, or a Pharmaceutical Composition as herein before described said second layer comprises a polymer; (b) an outer wall surrounding said two or more layers; and (c) an orifice in said outer wall (Pharmaceutical Composition P.5).

Composition P.5 preferably utilizes a semi-permeable membrane surrounding a three-layer-core: in these embodiments the first layer is referred to as a first drug layer and contains low amounts of drug (e.g., the Compound of Formulas I-IV et seq.) and an osmotic agent such as salt, the middle layer referred to as the second drug layer contains higher amounts of drug, excipients and no salt; and the third layer referred to as the push layer contains osmotic agents and no drug (Pharmaceutical Composition P.6). At least one orifice is drilled through the membrane on the first drug layer end of the capsule-shaped tablet.

Composition P.5 or P.6 may comprise a membrane defining a compartment, the membrane surrounding an inner protective subcoat, at least one exit orifice formed or formable therein and at least a portion of the membrane being semi-permeable; an expandable layer located within the compartment remote from the exit orifice and in fluid communication with the semi-permeable portion of the membrane; a first drug layer located adjacent the exit orifice; and a second drug layer located within the compartment between the first drug layer and the expandable layer, the drug layers comprising the Compound of the Invention in free or pharmaceutically acceptable salt thereof (Pharmaceutical Composition P.7). Depending upon the relative viscosity of the first drug layer and second drug layer, different release profiles are obtained. It is imperative to identify the optimum viscosity for each layer. In the present invention, viscosity is modulated by addition of salt, sodium chloride. The delivery profile from the core is dependent on the weight, formulation and thickness of each of the drug layers.

In a particular embodiment, the invention provides Pharmaceutical Composition P.7 wherein the first drug layer comprising salt and the second drug layer containing no salt. Pharmaceutical Composition P.5-P.7 may optionally comprise a flow-promoting layer between the membrane and the drug layers.

Pharmaceutical Compositions P.1-P.7 will generally be referred to as Osmotic-controlled Release Oral Delivery System Composition.

In an eighth aspect, the invention provides a method (Method 1) for the treatment or prophylaxis of a central nervous system disorder, comprising administering to a patient in need thereof a Compound of Formulas I-IV et seq. or a Pharmaceutical Composition 6 or 6.1-6.10 or P.1-P.7, for example Method 1 wherein the compound or composition administered is:

-   -   1.1 Compound I or any of 1.1-1.35, in free or pharmaceutically         acceptable salt form;     -   1.2 Compound II or any of 2.1-2.12, in free or pharmaceutically         acceptable salt form;     -   1.3 Compound III or any of 3.1-3.11, in free or pharmaceutically         acceptable salt form;     -   1.4 Compound IV or any of 4.1-4.11, in free or pharmaceutically         acceptable salt form;     -   1.5 The Compounds of Embodiment 5 or any of 5.1-5.5;     -   1.6 Compound of Formula II-A, II-B, or II-C in free or         pharmaceutically acceptable salt form, in admixture with a         pharmaceutically acceptable diluent or carrier;     -   1.7 Compound of Formula III-A, III-B or III-C, in free or         pharmaceutically acceptable salt form, in admixture with a         pharmaceutically acceptable diluent or carrier;     -   1.8 Compound of Formula IV-A, IV-B or IV-C, in free or         pharmaceutically acceptable salt form, in admixture with a         pharmaceutically acceptable diluent or carrier;     -   1.9 a Pharmaceutical Composition as described by any of         Compositions 6 and 6.1-6.10;     -   1.10 a Pharmaceutical Composition comprising a Compound of         Formula II-A, II-B, or II-C, in free or pharmaceutically         acceptable salt form, in admixture with a pharmaceutically         acceptable diluent or carrier;     -   1.11 a Pharmaceutical Composition comprising a Compound of         Formula III-A, III-B or III-C, in free or pharmaceutically         acceptable salt form, in admixture with a pharmaceutically         acceptable diluent or carrier;     -   1.12 a Pharmaceutical Composition comprising a Compound of         Formula IV-A, IV-B or IV-C, in free or pharmaceutically         acceptable salt form, in admixture with a pharmaceutically         acceptable diluent or carrier;     -   1.13 Depot Composition as described in Depot Composition 6.09 or         6.10;     -   1.14 Pharmaceutical Composition P.1-P.7;     -   1.15 Osmotic-controlled Release Oral Delivery System Composition         as hereinbefore described;

In a further embodiment of the eighth aspect, the present disclosure provides Method 1 or any of Methods 1.1-1.15, wherein the method is further as described as follows:

-   -   1.16 Method 1 or any of Methods 1.1-1.15, wherein the central         nervous system disorder is a disorder selected from a group         consisting of obesity, anxiety, depression (for example         refractory depression and MDD), psychosis (including psychosis         associated with dementia, such as hallucinations in advanced         Parkinson's disease or paranoid delusions), schizophrenia, sleep         disorders (particularly sleep disorders associated with         schizophrenia and other psychiatric and neurological diseases),         sexual disorders, migraine, conditions associated with cephalic         pain, social phobias, agitation in dementia (e.g., agitation in         Alzheimer's disease), agitation in autism and related autistic         disorders, gastrointestinal disorders such as dysfunction of the         gastrointestinal tract motility, and dementia, for example         dementia of Alzheimer's disease or of Parkinson's disease; mood         disorders; and drug dependencies, for example, opiate dependency         and/or alcohol dependency, or withdrawal from drug or alcohol         dependency (e.g., opiate dependency); or binge eating disorder;         or opiate overdose; or opiate use disorder (OUD);     -   1.17 Method 1 or any of Methods 1.1-1.16, wherein the central         nervous system disorder is a disorder involving serotonin         5-HT_(2A), dopamine D2 and/or D1 receptor system and/or         serotonin reuptake transporter (SERT) pathways as similarly         described in WO/2009/145900 and US 2011/071080, the contents of         which are herein incorporated by reference in their entirety;     -   1.18 Method 1 or any of Methods 1.1-1.17, wherein the central         nervous system disorder is a disorder involving the μ-opioid         receptor;     -   1.19 Method 1 or any of Methods 1.1-1.18, wherein the central         nervous system disorder is a disorder selected from the         following: (i) psychosis, e.g., schizophrenia, in a patient         suffering from depression; (2) depression in a patient suffering         from psychosis, e.g., schizophrenia; (3) mood disorders         associated with psychosis, e.g., schizophrenia or Parkinson's         disease; (4) sleep disorders associated with psychosis, e.g.,         schizophrenia or Parkinson's disease; and (5) substance         addiction, substance use disorders and/or substance-induced         disorders, optionally wherein the patient suffers from residual         symptoms of anxiety or anxiety disorder;     -   1.20 Method 1 or any of Methods 1.1-1.18, wherein the central         nervous system disorder is psychosis, e.g., schizophrenia and         said patient is a patient suffering from depression;     -   1.21 Method 1 or any of Methods 1.1-1.20, wherein said patient         is unable to tolerate the side effects of conventional         antipsychotic drugs, e.g., chlorpromazine, haloperidol,         droperidol, fluphenazine, loxapine, mesoridazine molindone,         perphenazine, pimozide, prochlorperazine promazine,         thioridazine, thiothixene, trifluoperazine, clozapine,         aripiprazole, olanzapine, quetiapine, risperidone and         ziprasidone;     -   1.22 Method 1 or any of Methods 1.1-1.20, wherein said patient         is unable to tolerate the side effects of conventional         antipsychotic drugs, e.g., haloperidol, aripiprazole, clozapine,         olanzapine, quetiapine, risperidone, and ziprasidone;     -   1.23 Method 1 or any of Methods 1.1-1.22, wherein said disorder         is depression and said patient is a patient suffering from         psychosis, e.g., schizophrenia, or Parkinson's disease;     -   1.24 Method 1 or any of Methods 1.1-1.22, wherein said disorder         is sleep disorder and said patient is suffering from depression;     -   1.25 Method 1 or any of Methods 1.1-1.22, wherein said one or         more disorders is sleep disorder and said patient is suffering         from psychosis, e.g., schizophrenia;     -   1.26 Method 1 or any of Methods 1.1-1.22, wherein said one or         more disorders is sleep disorder and said patient is suffering         from Parkinson's disease;     -   1.27 Method 1 or any of Methods 1.1-1.22, wherein said one or         more disorders is sleep disorder and said patient is suffering         from depression and psychosis, e.g., schizophrenia, or         Parkinson's disease.     -   1.28 Method 1 or any of 1.1-1.27, wherein said patient is         suffering from a drug dependency disorder, optionally in         conjunction with any preceding disorders, for example, wherein         said patient suffers from opiate dependency and/or alcohol         dependency, or from withdrawal from drug or alcohol dependency,         optionally wherein the patient suffers from residual symptoms of         anxiety or anxiety disorder; further optionally wherein the         patient suffers from an opiate overdose;     -   1.29 Any of the foregoing methods, wherein the effective amount         is 1 mg-1000 mg, preferably 2.5 mg-50 mg;     -   1.30 Any of the foregoing methods, wherein the effective amount         is 1 mg-100 mg per day, preferably 2.5 mg-50 mg per day;     -   1.31 Any of the foregoing methods wherein a condition to be         treated is dyskinesia, e.g. in a patient receiving dopaminergic         medications, e.g., medications selected from levodopa and         levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B         inhibitors), dopamine agonists, and anticholinergics, e.g.,         levodopa;     -   1.32 Any of the foregoing methods wherein the patient suffers         from Parkinson's disease.

Substance-use disorders and substance-induced disorders are the two categories of substance-related disorders defined by the Fifth Edition of the DSM (the Diagnostic and Statistical Manual of Mental Disorders, or DSM-V). A substance-use disorder is a pattern of symptoms resulting from use of a substance which the individual continues to take, despite experiencing problems as a result. A substance-induced disorder is a disorder induced by use if the substance. Substance-induced disorders include intoxication, withdrawal, substance induced mental disorders, including substance induced psychosis, substance induced bipolar and related disorders, substance induced depressive disorders, substance induced anxiety disorders, substance induced obsessive-compulsive and related disorders, substance induced sleep disorders, substance induced sexual dysfunctions, substance induced delirium and substance induced neurocognitive disorders.

The DSM-V includes criteria for classifying a substance use disorder as mild, moderate or severe. In some embodiments of the methods disclosed herein, the substance use disorder is selected from a mild substance use disorder, a moderate substance use disorder or a severe substance use disorder. In some embodiments, the substance use disorder is a mild substance use disorder. In some embodiments, the substance use disorder is a moderate substance use disorder. In some embodiments, the substance use disorder is a severe substance use disorder.

Anxiety is a highly prevalent co-morbid disorder in patients undergoing treatment of substance use or substance abuse. A common treatment for substance abuse disorder is the combination of the partial opioid agonist buprenorphine with the opioid antagonist naloxone, but neither of these drugs has any significant effect on anxiety, thus leading to the common result that a third drug, such as a benzodiazepine-class anxiolytic agent. This makes treatment regimens and patient compliance more difficult. In contrast, the Compounds of the present disclosure provide opiate antagonism along with serotonin antagonism and dopamine modulation. This may result in significant enhancement of treatment of patients with substance use or abuse disorder concomitant with anxiety. Depression is also a highly prevalent disorder in patients undergoing substance use or substance abuse treatment. Thus, antidepressants, such as SSRIs, are also often used concomitantly in patients undergoing substance abuse treatment. Compounds of the present disclosure may also enhance treatment in such patients by providing treatment for substance use or substance abuse as well as both anxiety and depression.

The compounds of the present disclosure may have anxiolytic properties ameliorating the need for treatment of a patient with an anxiolytic agent where said patients suffers from co-morbid anxiety. Thus, in some embodiments, the present disclosure provides a method according to Method 1, or any of Methods 1.1-1.32, wherein the central nervous system disorder is a substance addiction, substance use disorders and/or substance-induced disorders, or a substance abuse disorder, for example, in a patient suffering from symptoms of anxiety or who is diagnosed with anxiety as a co-morbid disorder, or as a residual disorder, wherein the method does not comprise the further administration of an anxiolytic agent, such as a benzodiazepine. Benzodiazepines are GABA-modulating compounds, including those discussed with reference to Method 3.1 and 3.2 below.

In another embodiment of the eighth aspect, the present disclosure provides Method 1 or any of Methods 1.1-1.15, wherein the method is further as described as follows:

-   -   1.33 Method 1 or any of Methods 1.1-1.32, wherein the central         nervous system disorder is a disorder selected from         obsessive-compulsive disorder (OCD), obsessive-compulsive         personality disorder (OCPD), general anxiety disorder, social         anxiety disorder, panic disorder, agoraphobia, compulsive         gambling disorder, compulsive eating disorder, body dysmorphic         disorder, hypochondriasis, pathological grooming disorder,         kleptomania, pyromania, attention deficit-hyperactivity disorder         (ADHD), attention deficit disorder (ADD), impulse control         disorder, and related disorders, and combination thereof.     -   1.34 Method 1 or any one Method 1.1-1.33, wherein the central         nervous system disorder is selected from obsessive-compulsive         disorder (OCD), obsessive-compulsive personality disorder         (OCPD), social anxiety disorder, panic disorder, agoraphobia,         compulsive gambling disorder, compulsive eating disorder, body         dysmorphic disorder and impulse control disorder.     -   1.35 Method 1 or any one of Method 1.1-1.33, wherein the central         nervous system disorder is obsessive-compulsive disorder (OCD)         or obsessive-compulsive personality disorder (OCPD).     -   1.36 Any foregoing method, wherein said patient is not         responsive to or cannot tolerate the side effects from,         treatment with selective serotonin reuptake inhibitors (SSRIs),         such as citalopram, escitalopram, fluoxetine, fluvoxamine,         paroxetine, and sertraline.     -   1.37 Any foregoing method, wherein said patient is not         responsive to or cannot tolerate the side effects from,         treatment with serotonin-norepinephrine reuptake inhibitors         (SNRIs), such as venlafaxine, sibutramine, duloxetine,         atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran.     -   1.38. Any foregoing method, wherein said patient is not         responsive to or cannot tolerate the side effects from,         treatment with antipsychotic agents, such as clomipramine,         risperidone, quetiapine and olanzapine.     -   1.39 Method 1 or any of Method 1.1-1.33, wherein the central         nervous system disorder is a pain disorder, e.g., a condition         associated with pain, such as cephalic pain, idiopathic pain,         neuropathic pain, chronic pain (e.g., moderate to moderately         severe chronic pain, for example, in patients requiring 24-hour         extended treatment for other ailments), fibromyalgia, dental         pain, traumatic pain, or chronic fatigue.     -   1.40 Any foregoing method, wherein the patient is not responsive         to or cannot tolerate the side effects of non-narcotic         analgesics and/or opiate and opioid drugs, or wherein the use of         opiate drugs are contraindicated in said patient, for example,         due to prior substance abuse or a high potential for substance         abuse, such as opiate and opioid drugs including, e.g.,         morphine, codeine, thebaine, oripavine, morphine dipropionate,         morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine,         hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl,         alpha-methylfentantyl, alfentanyl, trefantinil, brifentanil,         remifentanil, octfentanil, sufentanil, carfentanyl, meperidine,         prodine, promedol, propoxyphene, dextropropoxyphene, methadone,         diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol,         nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol,         and anileridine, or any combinations thereof;     -   1.41 Method I or any of Methods 1.1-1.40, wherein the central         nervous system disease or disorder is a drug dependency (for         example, opiate dependency (i.e., opioid use disorder), cocaine         dependency, amphetamine dependency, and/or alcohol dependency),         or withdrawal from drug or alcohol dependency (e.g., opiate,         cocaine, or amphetamine dependency), and wherein the patient         also suffers from a co-morbidity, such as anxiety, depression or         psychosis; optionally wherein the patient also suffers from an         opiate overdose;     -   1.42 Any of the foregoing methods, wherein the effective amount         is 1 mg-1000 mg, preferably 2.5 mg-50 mg;     -   1.43 Any of the foregoing methods, wherein the effective amount         is 1 mg-100 mg per day, preferably 2.5 mg-50 mg per day.

In another embodiment, the present disclosure provides Method 1 or any of Methods 1.1-1.32, or any of Methods 1.33-1.43, wherein the Compounds of Formulas I-IV et seq. or Pharmaceutical Composition 6 or 6.1-6.10 or P.1-P.7 comprises:

-   -   1.44 a Compound of Formula II-A, II-B, II-C or II-D, in free or         pharmaceutically acceptable salt form, in admixture with a         pharmaceutically acceptable diluent or carrier;     -   1.45 a Compound of Formula III-A, III-B or III-C in free or         pharmaceutically acceptable salt form, in admixture with a         pharmaceutically acceptable diluent or carrier; or     -   1.46 a Compound of Formula IV-A, IV-B or IV-C in free or         pharmaceutically acceptable salt form, in admixture with a         pharmaceutically acceptable diluent or carrier

In another embodiment of the eighth aspect, the invention provides Method 1, or any of Methods 1.1-1.46, e.g., any method of treating pain, wherein the patient suffers from a gastrointestinal disorder and/or a pulmonary disorder. Traditional opioid analgesics suffer from two dominant side effects: gastrointestinal disturbances (including nausea, vomiting and constipation) and respiratory depression. 90 to 95% of patients taking opioids for long-term pain treatment develop serious constipation, requiring the long-term use of laxatives and/or enemas. The stronger opioids such as morphine, oxycodone and hydromorphone produce more severe constipation than other opioids. Respiratory depression is the most serious adverse effect of opioid treatment as it creates a risk of death, especially when patients combine (intentionally or inadvertently) prescribed opioid analgesics with other licit or illicit respiratory depressants (including alcohol). Patients in need of pain treatment, especially chronic pain treatment, are therefore at particular risk of adverse effects if they suffer from a pre-existing gastrointestinal or pulmonary disorder. Unlike traditional opioid analgesics, the compounds of the present invention (e.g., the compound of Formula I, e.g., of Formula 1.31), provide analgesic relief without significant adverse gastrointestinal effects and without significant respiratory depression. Therefore, such compounds would provide improved safety and efficacy for patients in need of pain treatment having these preexisting GI and pulmonary disorders. In further embodiments, a compound of the present invention may be combined with a traditional opiate agent to provide improved pain control with a dose-sparing effect as to the traditional opiate agent (and concomitantly reduced risk of adverse effects).

Thus, in particular embodiments, the present invention further provides:

-   -   1.47 Method 1 or any of 1.1-1.46, wherein the patient suffers         from a pre-existing or co-morbid gastrointestinal disorder         and/or pulmonary disorder;     -   1.48 Method 1.47, wherein the pre-existing or co-morbid disorder         is selected from the group consisting of irritable bowel         syndrome, pelvic floor disorder, diverticulitis, inflammatory         bowel disease, colon or colorectal cancer, celiac disease,         non-celiac gluten sensitivity, asthma, chronic obstructive         pulmonary disease (COPD), dyspnea, pneumonia, congestive heart         failure, interstitial lung disease, pneumothorax, bronchitis,         pulmonary embolism, and traumatic chest injury (e.g., broken         sternum or ribs, bruised intercostal muscles);     -   1.49 Method 1.47 or 1.48 wherein the central nervous system         disorder is a pain disorder, e.g., a condition associated with         pain, such as cephalic pain, idiopathic pain, neuropathic pain,         chronic pain (e.g., moderate to moderately severe chronic pain,         for example, in patients requiring 24-hour extended treatment         for other ailments), fibromyalgia, dental pain, traumatic pain,         or chronic fatigue;     -   1.50 Any of Method 1 or 1.1-1.49, wherein the central nervous         system disorder is opiate use disorder, opiate withdrawal or         opiate dependency, and wherein the method provides relief from         withdrawal-induced symptoms (e.g., gastrointestinal symptoms         such as diarrhea, anxiety, depression, pain, sleep disturbances,         or any combination thereof);     -   1.51 Any of Method 1 or 1.1-1.50, wherein the method further         comprises the concurrent administration of another opiate or         opioid agent, e.g., administered simultaneously, separately or         sequentially;     -   1.52 Method 1.51, wherein the additional opiate or opioid agent         is selected from the group consisting of morphine, codeine,         thebaine, oripavine, morphine dipropionate, morphine         dinicotinate, dihydrocodeine, buprenorphine, etorphine,         hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl,         alpha-methylfentantyl, alfentanyl, trefantinil, brifentanil,         remifentanil, octfentanil, sufentanil, carfentanyl, meperidine,         prodine, promedol, propoxyphene, dextropropoxyphene, methadone,         diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol,         nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol,         and anileridine, or any combinations thereof;     -   1.53 Any of Method 1 or 1.1-1.52, wherein the method further         comprises the concurrent administration of a NMDA receptor         antagonist, e.g., administered simultaneously, separately or         sequentially;     -   1.54 Method 1.53, wherein the NMDA receptor antagonist is         selected from the group consisting of ketamine (e.g., S-ketamine         and/or R-ketamine), hydroxynorketamine, memantine,         dextromethorphan, dextroallorphan, dextrorphan, amantadine, and         agmatine, or any combination thereof;     -   1.55 Any of methods 1.47-1.54, wherein the compound is the         compound of Formula I, wherein X is —NH—, L is O, and Z is —O—.

In still another embodiment, the present disclosure provides any of the Methods 1 or 1.1-1.55 as hereinbefore described wherein the disorder is schizophrenia or sleep disorder. In some embodiments, said schizophrenia is associated with depression.

In still another embodiment, the present disclosure provides any of Methods 1.1-1.55, wherein the Depot Composition of the Invention (e.g., Depot Composition of any of formulae 6.8-6.10), or (Pharmaceutical) Composition 6 or 6.1-6.7, or Pharmaceutical Composition P.1-P.7, is administered for controlled- and/or sustained-release of the Compounds of the Invention over a period of from about 14 days, about 30 to about 180 days, preferably over the period of about 30, about 60 or about 90 days. Controlled- and/or sustained-release is particularly useful for circumventing premature discontinuation of therapy, particularly for antipsychotic drug therapy.

In still another embodiment, the invention provides any Method 1 or 1.1-1.55 as hereinbefore described, wherein the Depot Composition of the present disclosure is administered for controlled- and/or sustained-release of the Compounds of the Invention over a period of time.

In a ninth aspect, the invention provides a method (Method 2) for the prophylaxis or treatment of one or more sleep disorders comprising administering to a patient in need thereof a Compound of Formulas I-IV et seq. or a Pharmaceutical Composition 6 or 6.1-6.10 or P.1-P.7, (Method 2) for example Method 2 wherein the compound or composition administered is:

-   -   2.1 Compound I or 1.1-1.35, in free or pharmaceutically         acceptable salt form;     -   2.2 Compound II or 2.1-2.12, in free or pharmaceutically         acceptable salt form;     -   2.3 Compound III or 3.1-3.11, in free or pharmaceutically         acceptable salt form;     -   2.4 Compound IV or 4.1-4.11, in free or pharmaceutically         acceptable salt form;     -   2.5 Compound 5 or 5.1-5.5;     -   2.6 Compound of Formula II-A, II-B, II-C or II-D, in free or         pharmaceutically acceptable salt form, in admixture with a         pharmaceutically acceptable diluent or carrier;     -   2.7 Compound of Formula III-A, III-B or III-C, in free or         pharmaceutically acceptable salt form, in admixture with a         pharmaceutically acceptable diluent or carrier;     -   2.8 Compound of Formula IV-A, IV-B or IV-C, in free or         pharmaceutically acceptable salt form, in admixture with a         pharmaceutically acceptable diluent or carrier;     -   2.9 a Pharmaceutical Composition as described by any of         Compositions 6 and 6.1-6.10;     -   2.10 a Pharmaceutical Composition comprising a Compound of         Formula II-A, II-B, or II-C, in free or pharmaceutically         acceptable salt form, in admixture with a pharmaceutically         acceptable diluent or carrier;     -   2.11 a Pharmaceutical Composition comprising a Compound of         Formula III-A, III-B or III-C, in free or pharmaceutically         acceptable salt form, in admixture with a pharmaceutically         acceptable diluent or carrier;     -   2.12 a Pharmaceutical Composition comprising a Compound of         Formula IV-A, IV-B or IV-C, in free or pharmaceutically         acceptable salt form, in admixture with a pharmaceutically         acceptable diluent or carrier;     -   2.13 Depot Composition as described in Depot Composition 6.09 or         6.10;     -   2.14 Pharmaceutical Composition P.1-P.7;     -   2.15 Osmotic-controlled Release Oral Delivery System Composition         as hereinbefore described;

In a further embodiment of the ninth aspect, the invention provides Method 2, or 2.1-2.15, wherein the sleep disorder includes sleep maintenance insomnia, frequent awakenings, and waking up feeling unrefreshed; for example:

-   -   2.16 Any of the foregoing methods, wherein the sleep disorder is         sleep maintenance insomnia;     -   2.17 Any of the foregoing methods, wherein the effective amount         is 1 mg-5 mg, preferably 2.5-5 mg, per day;     -   2.18 Any of the foregoing methods, wherein the effective amount         is 2.5 mg or 5 mg, per day;     -   2.19 Any of the foregoing methods wherein the sleep disorder is         in a patient suffering from or at risk of dyskinesia, e.g., a         patient receiving dopaminergic medications, e.g., selected from         levodopa and levodopa adjuncts (carbidopa, COMT inhibitors,         MAO-B inhibitors), dopamine agonists, and anticholinergics,         e.g., receiving levodopa;     -   2.20 Any of the foregoing methods wherein the patient suffers         from Parkinson's disease.

In a further embodiment of the ninth aspect, the invention provides Method 2, or any of 2.1-2.20, wherein the sleep disorder includes sleep maintenance insomnia, frequent awakenings, and waking up feeling unrefreshed.

The Compounds of the present disclosure, the Pharmaceutical Compositions of the present disclosure or the Depot Compositions of the present disclosure may be used in combination with a second therapeutic agent, particularly at lower dosages than when the individual agents are used as a monotherapy so as to enhance the therapeutic activities of the combined agents without causing the undesirable side effects commonly occur in conventional monotherapy. Therefore, the Compounds of the present disclosure may be simultaneously, sequentially, or contemporaneously administered with other anti-depressant, anti-psychotic, other hypnotic agents, and/or agents use to treat Parkinson's disease or mood disorders. In another example, side effects may be reduced or minimized by administering a Compound of the present disclosure in combination with one or more second therapeutic agents in free or salt form, wherein the dosages of (i) the second therapeutic agent(s) or (ii) both Compound of the present disclosure and the second therapeutic agents, are lower than if the agents/compounds are administered as a monotherapy. In a particular embodiment, the Compounds of the present disclosure are useful to treat dyskinesia in a patient receiving dopaminergic medications, e.g., selected from levodopa and levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergics, e.g., such as are used in the treatment of Parkinson's disease.

In some further embodiments of the present disclosure, the Pharmaceutical Compositions of the present disclosure or the Depot Compositions of the present disclosure may be used in combination with a second therapeutic agent, particularly at lower dosages than when the individual agents are used as a monotherapy so as to enhance the therapeutic activities of the combined agents without causing the undesirable side effects, wherein the second therapeutic agent is an opiate antagonist (e.g., naloxone). The Compounds of the present disclosure may be simultaneously, sequentially, or contemporaneously administered with such opiate antagonists.

Therefore, in a tenth aspect, the present disclosure provides Method 1, or any of Methods 1.1-1.55, or Method 2 or any of 2.1-2.20, further comprising the administration of one or more therapeutic agents to the patient, wherein the one or more therapeutic agents are selected from compounds that modulate GABA activity (e.g., enhances the activity and facilitates GABA transmission), a GABA-B agonist, a 5-HT receptor modulator (e.g., a 5-HT_(1A) agonist, a 5-HT_(2A) antagonist, a 5-HT_(2A) inverse agonist, etc.), a melatonin receptor agonist, an ion channel modulator (e.g., blocker), a serotonin-2 antagonist/reuptake inhibitor (SARIs), an orexin receptor antagonist, an H3 agonist or antagonist, a noradrenergic agonist or antagonist, a galanin agonist, a CRH antagonist, human growth hormone, a growth hormone agonist, estrogen, an estrogen agonist, a neurokinin-1 drug, an anti-depressant, an opiate agonist and/or partial opiate agonist, an opiate antagonist and/or opiate inverse agonist, and an antipsychotic agent, e.g., an atypical antipsychotic agent, in free or pharmaceutically acceptable salt form (Method 1-A and 2-A respectively; collectively, “Method 3”).

In further embodiments of the tenth aspect, the present disclosure provides Method 1, or any of Methods 1.1-1.55, or Method 2 or any of 2.1-2.20, further comprising the administration to the patient of one or more therapeutic agents selected from the foregoing and further selected from agonists or partial agonists, or inverse agonists or antagonists, of the mu-opiate, kappa-opiate, delta-opiate, and/or nociceptin/orphanin receptors. In further embodiments of the tenth aspect, the present disclosure also provides Method 1, or any of Methods 1.1-55, or Method 2 or any of 2.1-2.20, further comprising the administration to the patient of one or more therapeutic agents selected from a serotonin HT6 receptor antagonist, and an mGluR-2, -3 or -5 receptor agonist or antagonist (including both positive and negative modulators and partial agonists).

In a further embodiment of the tenth aspect, the invention provides Method 3 (i.e., Method 1-A or 2-A), wherein the method further comprises the administration to the patient of one or more therapeutic agents, as follows:

-   -   3.1 Method 1-A or 2-A, wherein the therapeutic agent(s) is         compounds that modulate GABA activity (e.g., enhances the         activity and facilitates GABA transmission);     -   3.2 Method 1-A or 2-A or 3.1, wherein the GABA compound is         selected from a group consisting of one or more of doxepin,         alprazolam, bromazepam, clobazam, clonazepam, clorazepate,         diazepam, flunitrazepam, flurazepam, lorazepam, midazolam,         nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone,         eszopiclone, zaleplon, Zolpidem, gaboxadol, vigabatrin,         tiagabine, EVT 201 (Evotec Pharmaceuticals) and estazolam;     -   3.3 Method 1-A or 2-A, wherein the therapeutic agent is an         additional 5HT2a antagonist;     -   3.4 Method 1-A or 2-A or 3.3, wherein said additional 5HT2a         antagonist is selected from one or more of ketanserin,         risperidone, eplivanserin, volinanserin (Sanofi-Aventis,         France), pruvanserin, MDL 100907 (Sanofi-Aventis, France), HY         10275 (Eli Lilly), APD 125 (Arena Pharmaceuticals, San Diego,         Calif.), and AVE8488 (Sanofi-Aventis, France);     -   3.5 Method 1-A or 2-A, wherein the therapeutic agent is a         melatonin receptor agonist;     -   3.6 Method 1-A or 2-A or 3.5, wherein the melatonin receptor         agonist is selected from a group consisting of one or more of         melatonin, ramelteon (ROZEREM®, Takeda Pharmaceuticals, Japan),         VEC-162 (Vanda Pharmaceuticals, Rockville, Md.), PD-6735 (Phase         II Discovery) and agomelatine;     -   3.7 Method 1-A or 2-A, wherein the therapeutic agent is an ion         channel blocker;     -   3.8 Method 1-A or 2-A or 3.7, wherein said ion channel blocker         is one or more of lamotrigine, gabapentin and pregabalin;     -   3.9 Method 1-A or 2-A, wherein the therapeutic agent is an         orexin receptor antagonist;     -   3.10 Method 1-A or 2-A or 3.9, wherein the orexin receptor         antagonist is selected from a group consisting of orexin, a         1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), GW649868         (GlaxoSmithKline) and a benzamide derivative;     -   3.11 Method 1-A or 2-A, wherein the therapeutic agent is the         serotonin-2 antagonist/reuptake inhibitor (SARI);     -   3.12 Method 1-A or 2-A or 3.11, wherein the serotonin-2         antagonist/reuptake inhibitor (SARI) is selected from a group         consisting of one or more Org 50081 (Organon—Netherlands),         ritanserin, nefazodone, serzone and trazodone;     -   3.13 Method 1-A or 2-A, wherein the therapeutic agent is the         5HTIa agonist;     -   3.14 Method 1-A or 2-A or 3.13, wherein the 5HTIa agonist is         selected from a group consisting of one or more of repinotan,         sarizotan, eptapirone, buspirone and MN-305 (MediciNova, San         Diego, Calif.);     -   3.15 Method 1-A or 2-A, wherein the therapeutic agent is the         neurokinin-1 drug;     -   3.16 Method 1-A or 2-A or 3.15, wherein the neurokinin-1 drug is         Casopitant (GlaxoSmithKline);     -   3.17 Method 1-A or 2-A, wherein the therapeutic agent is an         antipsychotic agent;     -   3.18 Method 1-A or 2-A or 3.17, wherein the antipsychotic agent         is selected from a group consisting of chlorpromazine,         haloperidol, droperidol, fluphenazine, loxapine, mesoridazine,         molindone, perphenazine, pimozide, prochlorperazine promazine,         thioridazine, thiothixene, trifluoperazine, clozapine,         aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone         and paliperidone;     -   3.19 Method 1-A or 2-A, wherein the therapeutic agent is an         anti-depressant;     -   3.20 Method 1-A or 2-A or 3.19, wherein the anti-depressant is         selected from amitriptyline, amoxapine, bupropion, citalopram,         clomipramine, desipramine, doxepin, duloxetine, escitalopram,         fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline,         mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine         sulfate, protriptyline, sertraline, tranylcypromine, trazodone,         trimipramine, and venlafaxine;     -   3.21 Method 1-A or 2-A, 3.17 or 3.18, wherein the antipsychotic         agent is an atypical antipsychotic agent;     -   3.22 Method 1-A or 2-A, or any of 3.17-3.21, wherein the         atypical antipsychotic agent is selected from a group consisting         of clozapine, aripiprazole, olanzapine, quetiapine, risperidone,         ziprasidone, and paliperidone;     -   3.23 Method 1-A or 2-A, wherein the therapeutic agent is         selected from any of methods 3.1-3.22, e.g., selected from a         group consisting of modafinil, armodafinil, doxepin, alprazolam,         bromazepam, clobazam, clonazepam, clorazepate, diazepam,         flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam,         oxazepam, temazepam, triazolam, indiplon, zopiclone,         eszopiclone, zaleplon, Zolpidem, gaboxadol, vigabatrin,         tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam,         ketanserin, risperidone, eplivanserin, volinanserin         (Sanofi-Aventis, France), pruvanserin, MDL 100907         (Sanofi-Aventis, France), HY 10275 (Eli Lilly), APD 125 (Arena         Pharmaceuticals, San Diego, Calif.), AVE8488 (Sanofi-Aventis,         France), repinotan, sarizotan, eptapirone, buspirone, MN-305         (MediciNova, San Diego, Calif.), melatonin, ramelteon (ROZEREM®,         Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals,         Rockville, Md.), PD-6735 (Phase II Discovery), agomelatine,         lamotrigine, gabapentin, pregabalin, orexin, a 1,3-biarylurea,         SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline), a         benzamide derivative, Org 50081 (Organon—Netherlands),         ritanserin, nefazodone, serzone, trazodone, Casopitant         (GlaxoSmithKline), amitriptyline, amoxapine, bupropion,         citalopram, clomipramine, desipramine, doxepin, duloxetine,         escitalopram, fluoxetine, fluvoxamine, imipramine,         isocarboxazid, maprotiline, mirtazapine, nefazodone,         nortriptyline, paroxetine, phenelzine sulfate, protriptyline,         sertraline, tranylcypromine, trazodone, trimipramine,         venlafaxine, chlorpromazine, haloperidol, droperidol,         fluphenazine, loxapine, mesoridazine, molindone, perphenazine,         pimozide, prochlorperazine promazine, thioridazine, thiothixene,         trifluoperazine, clozapine, aripiprazole, olanzapine,         quetiapine, risperidone, ziprasidone and paliperidone;     -   3.24 Method 1-A or 2-A wherein the therapeutic agent is an H3         agonist;     -   3.25 Method 1-A or 2-A, wherein the therapeutic agent is an H3         antagonist;     -   3.26 Method 1-A or 2-A, wherein the therapeutic agent is a         noradrenergic agonist or antagonist;     -   3.27 Method 1-A or 2-A, wherein the therapeutic agent is a         galanin agonist;     -   3.28 Method 1-A or 2-A, wherein the therapeutic agent is a CRH         antagonist;     -   3.29 Method 1-A or 2-A, wherein the therapeutic agent is a human         growth hormone;     -   3.30 Method 1-A or 2-A, wherein the therapeutic agent is a         growth hormone agonist;     -   3.31 Method 1-A or 2-A, wherein the therapeutic agent is         estrogen;     -   3.32 Method 1-A or 2-A, wherein the therapeutic agent is an         estrogen agonist;     -   3.33 Method 1-A or 2-A, wherein the therapeutic agent is a         neurokinin-1 drug;     -   3.34 Method 1-A or 2-A, wherein a therapeutic agent is combined         with compounds of Formula (I) and the therapeutic agent is an         anti-Parkinson agent such as L-dopa, co-careldopa, duodopa,         stalevo, Symmetrel, benztropine, biperiden, bromocriptine,         entacapone, pergolide, pramipexole, procyclidine, ropinirole,         selegiline and tolcapone;     -   3.35 Method 1-A or 2-A, wherein the therapeutic agent is an         opiate agonist or partial opiate agonist, for example, a         mu-agonist or partial agonist, or a kappa-agonist or partial         agonist, including mixed agonist/antagonists (e.g., an agent         with partial mu-agonist activity and kappa-antagonist activity);     -   3.36 Method 3.35, wherein the therapeutic agent is         buprenorphine, optionally, wherein said method does not include         co-treatment with an anxiolytic agent, e.g., a GABA compound or         benzodiazepine;     -   3.37 Method 1-A or 2-A, wherein compounds of Formula (I) may be         used to treat sleep disorders, depression, psychosis, or any         combinations thereof, in patients suffering from the listed         diseases and/or Parkinson's disease;     -   3.38 Method 1-A or 2-A, wherein the disorder is selected from at         least one or more of psychosis, e.g., schizophrenia, depression,         mood disorders, sleep disorders (e.g., sleep maintenance and/or         sleep onset) or any combination of disorders thereof;     -   3.39 Method 1-A or 2-A, wherein the therapeutic agent(s) is an         opiate receptor antagonist or inverse agonist, e.g, a full         opiate antagonist, for example, selected from naloxone,         naltrexone, nalmefene, methadone, nalorphine, levallorphan,         samidorphan, nalodeine, cyprodime, or norbinaltorphimine.     -   3.40 Any of the foregoing methods wherein the disorder is sleep         disorder;     -   3.41 Any of the foregoing methods, wherein the disorder is sleep         disorder associated with psychosis, e.g., schizophrenia or         Parkinson's disease; in free or pharmaceutically acceptable salt         form.

In an eleventh aspect of the invention, the combination of a Compound of the present disclosure and one or more second therapeutic agents as described in Methods 1-A, 2-A or any of Methods 3 or 3.1-3.41 may be administered to the patient as a Pharmaceutical Composition or a depot Composition as hereinbefore described. The combination compositions can include mixtures of the combined drugs, as well as two or more separate compositions of the drugs, which individual compositions can be, for example, co-administered together to a patient.

In a particular embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41 comprises administering to a patient in need thereof, a Compound of the Invention in combination with an atypical antipsychotic agent, e.g., a compound selected from clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, or paliperidone, in free or pharmaceutically acceptable salt form, for example wherein the dosage of the atypical antipsychotic agent is reduced and/or side effects are reduced.

In another embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41 comprises administering to a patient in need thereof, a Compound of the Invention in combination with an anti-depressant, e.g., amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, or venlafaxine, in free or pharmaceutically acceptable salt form. Alternatively, the anti-depressant may be used as an adjunct medication in addition to the compound of the Invention.

In still another embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41 comprises administering to a patient in need thereof, a Compound of the Invention in combination with a compound that modulates GABA activity, e.g., a compound selected from doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem, gaboxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam or any combinations thereof, in free or pharmaceutically acceptable salt form. In other embodiments, the methods disclosed herein do not further comprise administration of an GABA compound, a benzodiazepine or any other anxiolytic agent.

In another preferred embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41 comprises administering to a patient in need thereof, a Compound of the Invention in combination with doxepin in free or pharmaceutically acceptable salt form. Dosages of doxepin can vary in any range known to a person of ordinary skill in the art. In one example, a 10 mg dose of doxepin may be combined with any dosage of a compound of the Invention.

In another embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41 comprises administering to a patient in need thereof, a Compound of the Invention in combination (including as part of a daily dosage regimen) with an atypical stimulant, e.g., a modafinil, adrafinil, or armodafinil. A regimen incorporating a Compound of the Invention with such drugs promotes more regular sleep, and avoids side effects such as psychosis or mania associated with higher levels of such drugs, e.g., in the treatment of bipolar depression, cognition associated with schizophrenia, and excessive sleepiness and fatigue in conditions such as Parkinson's disease and cancer.

In another embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41 comprises administering to a patient in need thereof, a Compound of the Invention in combination (including as part of a daily dosage regimen) with an opiate receptor antagonist or inverse agonist, e.g., a full opiate antagonist, for example, selected from naloxone, naltrexone, nalmefene, methadone, nalorphine, levallorphan, samidorphan, nalodeine, cyprodime, or norbinaltorphimine.

In some of the foregoing embodiments, of each of the Compounds of Formulas I-IV et seq.; Pharmaceutical Compositions 6 and 6.1-6.8; Depo Compositions 6.9 and 6.10; Pharmaceutical Compositions P.1-P.7; Methods 1 and 1.1-1.55; and Methods 2 and 2.1-2.20; the compound of the present disclosure is substantially free of the compound of Formula A and/or substantially free of the compound of Formula B.

In a twelfth aspect, the invention provides use of a compound as described in the following:

-   -   11.1 Compound I or 1.1-1.35, in free or pharmaceutically         acceptable salt form;     -   11.2 Compound II or 2.1-2.12, in free or pharmaceutically         acceptable salt form;     -   11.3 Compound III or 3.1-3.11, in free or pharmaceutically         acceptable salt form;     -   11.4 Compound IV or 4.1-4.11, in free or pharmaceutically         acceptable salt form;     -   11.5 Compound 5 or 5.1-5.5;     -   11.6 a Compound of Formula II-A, II-B, II-C, II-D, or II-E in         free or pharmaceutically acceptable salt form;     -   11.7 a Compound of Formula III-A, III-B or III-C, in free or         pharmaceutically acceptable salt form;     -   11.8 a Compound of Formula IV-A, IV-B or IV-C, in free or         pharmaceutically acceptable salt form;     -   11.9 Pharmaceutical Composition 6 and 6.1-6.10;     -   11.10 Pharmaceutical Composition P.1-P.7;     -   11.11 Osmotic-controlled Release Oral Delivery System         Composition as hereinbefore described;         (in the manufacture of a medicament) for the treatment or         prophylaxis of one or more disorders as disclosed hereinbefore,         e.g., in any of Method 1 or 1.1-1.55, any of Method 2 and         2.1-2.20, and Method 3 or 3.3-3.41, or any methods described in         the eleventh aspect of the invention.

In the thirteenth aspect, the invention provides a pharmaceutical composition as hereinbefore described, e.g.:

-   -   12.1 Pharmaceutical Composition 6 and 6.1-6.10;     -   12.2 Pharmaceutical Composition P.1-P.7;     -   12.3 Osmotic-controlled Release Oral Delivery System Composition         as hereinbefore described,

for use in the treatment or prophylaxis of one or more disorders as disclosed hereinbefore, e.g., in any of Methods 1 and 1.1-1.55, Methods 2 and 2.1-2.20, Methods 1-A, 2-A, 3 or 3.1-3.41 or any methods described in the eleventh or twelfth aspect of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the mu-receptor antagonist activity of the compound of Example 3 compared to naloxone, as described in Example 10.

FIG. 2 shows the mu-receptor agonist activity of the compounds of Examples 1 and 3 compared to DAMGO and buprenorphine, as described in Example 10.

DETAILED DESCRIPTION OF THE INVENTION

If not otherwise specified or clear from context, the following terms as used herein have the following meetings:

“Alkyl” as used herein is a saturated or unsaturated hydrocarbon moiety, e.g., one to twenty-one carbon atoms in length, which may be linear or branched (e.g., n-butyl or tert-butyl), preferably linear, unless otherwise specified. For example, “C₁₋₂₁ alkyl” denotes alkyl having 1 to 21 carbon atoms. In one embodiment, alkyl is optionally substituted with one or more hydroxy or C₁₋₂₂alkoxy (e.g., ethoxy) groups. In another embodiment, alkyl contains 1 to 21 carbon atoms, preferably straight chain and optionally saturated or unsaturated, for example in some embodiments wherein R₁ is an alkyl chain containing 1 to 21 carbon atoms, preferably 6-15 carbon atoms, 16-21 carbon atoms, e.g., so that together with the —C(O)— to which it attaches, e.g., when cleaved from the compound of Formula I, forms the residue of a natural or unnatural, saturated or unsaturated fatty acid.

The term “pharmaceutically acceptable diluent or carrier” is intended to mean diluents and carriers that are useful in pharmaceutical preparations, and that are free of substances that are allergenic, pyrogenic or pathogenic, and that are known to potentially cause or promote illness. Pharmaceutically acceptable diluents or carriers thus exclude bodily fluids such as example blood, urine, spinal fluid, saliva, and the like, as well as their constituent components such as blood cells and circulating proteins. Suitable pharmaceutically acceptable diluents and carriers can be found in any of several well-known treatises on pharmaceutical formulations, for example Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, N.Y., 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington's Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; and Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.

The terms “purified,” “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g., from a reaction mixture), or natural source or combination thereof. Thus, the term “purified,” “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization, LC-MS and LC-MS/MS techniques and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.

The Compounds of Formula I, wherein Z is —(C═O)— or —(CH(OH))—, including for example the Compounds of Formulae II-B and II-C, may be produced as metabolites of a compound of Formula A, and/or as metabolites of a compound of Formula B:

The compound of Formula A is known to provide effective treatment of 5-HT_(2A), SERT and/or D₂ receptor related disorders without significant extrapyramidal side effects, as similarly disclosed and claimed in WO 2009/145900 and US 2011/0071080, the contents of which are incorporated by reference in their entirety. The plasma levels of compounds of Formulas II-B and II-C produced from metabolism of a compound of Formula A are, however, quite low and probably do not contribute significantly to the therapeutic activity of the compound of Formula A. Compounds of Formulae II-D and II-E could also be present as metabolites, although this has so far not been detected. The Compounds of Formula I have unexpectedly been found to have activity as antagonists of the μ-opioid receptor. This is unexpected because the compound of Formula A has not been known or understood to have any μ-opioid receptor activity or binding. Compounds of Formula I wherein X is —NH— and wherein L is —O— are shown to have particularly good μ-opioid receptor antagonism. Such Compounds of Formula I may therefore be useful in the treatment of drug dependency, such as opiate dependency and/or alcohol dependency, by inhibiting the endogenous opiate response to illicit drug administration, as well as by inhibiting the direct effects of ingestion of illicit opiate drugs.

It is surprising that metabolites of a compound of Formula A have somewhat different relative receptor binding affinity that compounds of Formula A. For example, the receptor binding profile of the compound for Formula II-B is very unique, with a combination of antagonist activities at 5-HT_(2A), D₁ and Mu opiate receptors, making this compound very interesting for treating mood disorders. The compound of Formula A is not active at the Mu opiate receptor, for example.

It has also unexpectedly been found that compounds according to Formula I, particularly wherein X is —NH, L is O, and Z is —O—, demonstrate potent 5-HT_(2A), D₁ and Mu opiate antagonism, along with moderate D₁, D₂ and SERT antagonism. Furthermore, it has been unexpectedly found that such compounds may operate as “biased” Mu opiate ligands. This means that when the compounds bind to Mu opiate receptors, they may operate as partial Mu agonists via G-protein coupled signaling, but as Mu antagonists via beta-arrestin signaling. This is in contrast to the traditional opiate agonists morphine and fentanyl, which tend to strongly activate both G-protein signaling and beta-arrestin signaling. The activation of beta-arrestin signaling by such drugs is thought to mediate the gastrointestinal dysfunction and respiratory suppression typically mediated by opiate drugs. Compounds according to the present invention, in particular compounds according to Formula I, are therefore expected to result in pain amelioration with less severe gastrointestinal and respiratory side effects than existing opiate analgesics. This effect has been shown in pre-clinical studies and Phase II and Phase III clinical trials of the biased Mu agonist oliceridine. Oliceridine has been shown to result in biased mu agonism via G-protein coupled signaling with reduced beta-arresting signaling compared to morphine, and this has been linked to its ability to produce analgesia with reduced respiratory side effects compared to morphine. Furthermore, because compounds according to the present antagonize the beta-arrestin pathway, they are expected to be useful in treating opiate overdose, because they will inhibit the most severe opiate adverse effects while still providing pain relief. Furthermore, the Compounds of the present disclosure also have sleep maintenance effect due to their serotonergic activity. As many people suffering from chronic pain have difficulty sleeping due to the pain, these compounds can help such patients sleep through the night due to the synergistic effects of serotonergic and opiate receptor activities.

Thus, in certain embodiments, the Compounds of the present disclosure may be used in a method of treating opiate use disorder (OUD), opiate overdose, or opiate withdrawal, either alone, or in conjunction with an opiate antagonist or inverse agonist (e.g., naloxone or naltrexone). It is particularly noteworthy that the Compounds of the present disclosure (e.g., the compound of Formula I, wherein X is —NH, L is O, and Z is —O—), shows a strong ability to mitigate the dysphoria and psychiatric comorbidities associated with drug withdrawal (e.g., mood and anxiety disorders, sleep disturbances), and it also provides potent analgesia but without the adverse effects (e.g., GI effects and pulmonary depression) and abuse potential seen with other opioid treatments (e.g., oxycodone, methadone or buprenorphine). Data suggests the unique pharmacologic profile of these compounds will also mitigate the risks of adverse drug-drug interactions (e.g., alcohol). These compounds are therefore particularly suited to treat opiate use disorder and the symptoms associated with opiate withdrawal. In addition, to the compounds' direct effect on mu receptor activity, the compounds' effect on serotonergic pathways results in anti-depressant, sleep maintenance, and anxiolytic effects. Because depression and anxiety are key factors leading susceptible patients to opioid use in the first place, the compounds of the present disclosure would both reduce the symptoms of opiate withdrawal at the same time that they reduce the psychiatric co-morbidities which promote opioid use—a two-pronged strategy to reduce the risk of remission. The sleep maintenance provided by these compounds would further improve the quality of life of patients undergoing OUD treatment.

Unless otherwise indicated, the Compounds of the present disclosure, e.g., Compound I or 1.1-1.35, Compound II or 2.1-2.18, Compound III or 3.1-3.13, or Compound IV or 4.1-4.13 (collectively, Compounds of Formulas I-IV et seq.) may exist in free or salt, e.g., as acid addition salts, form. An acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, acid acetic, trifluoroacetic, citric, maleic acid, toluene sulfonic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic acid, and the like. In addition, a salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)-amine. In a particular embodiment, the salt of the Compounds of the Invention is a toluenesulfonic acid addition salt. In another particular embodiment, the salt of the Compounds of the Invention is a fumaric acid addition salt. In a particular embodiment, the salt of the Compounds of the Invention is a phosphoric acid addition salt.

The Compounds of the present disclosure are intended for use as pharmaceuticals, therefore pharmaceutically acceptable salts are preferred. Salts which are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free Compounds of the Invention and are therefore also included within the scope of the compounds of the present disclosure.

The Compounds of the present disclosure may comprise one or more chiral carbon atoms. The compounds thus exist in individual isomeric, e.g., enantiomeric or diastereomeric form or as mixtures of individual forms, e.g., racemic/diastereomeric mixtures. Any isomer may be present in which the asymmetric center is in the (R)-, (S)-, or (R,S)-configuration. The invention is to be understood as embracing both individual optically active isomers as well as mixtures (e.g., racemic/diastereomeric mixtures) thereof. Accordingly, the Compounds of the Invention may be a racemic mixture or it may be predominantly, e.g., in pure, or substantially pure, isomeric form, e.g., greater than 70% enantiomeric/diastereomeric excess (“ee”), preferably greater than 80% ee, more preferably greater than 90% ee, most preferably greater than 95% ee. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, simulated moving bed and the like).

Geometric isomers by nature of substituents about a double bond or a ring may be present in cis (Z) or trans (E) form, and both isomeric forms are encompassed within the scope of this invention.

It is also intended that the compounds of the present disclosure encompass their stable and unstable isotopes. Stable isotopes are nonradioactive isotopes which contain one additional neutron compared to the abundant nuclides of the same species (i.e., element). It is expected that the activity of compounds comprising such isotopes would be retained, and such compound would also have utility for measuring pharmacokinetics of the non-isotopic analogs. For example, the hydrogen atom at a certain position on the compounds of the disclosure may be replaced with deuterium (a stable isotope which is non-radioactive). Examples of known stable isotopes include, but not limited to, deuterium, ¹³C, ¹⁵N, ¹⁸O. Alternatively, unstable isotopes, which are radioactive isotopes which contain additional neutrons compared to the abundant nuclides of the same species (i.e., element), e.g., ¹²³I, ¹³¹I, ¹²⁵I, ¹¹C, ¹⁸F, may replace the corresponding abundant species of I, C and F. Another example of useful isotope of the compound of the invention is the ¹¹C isotope. These radio isotopes are useful for radio-imaging and/or pharmacokinetic studies of the compounds of the invention. In addition, the substitution of atoms of having the natural isotopic distributing with heavier isotopes can result in desirable change in pharmacokinetic rates when these substitutions are made at metabolically liable sites. For example, the incorporation of deuterium (²H) in place of hydrogen can slow metabolic degradation when the position of the hydrogen is a site of enzymatic or metabolic activity.

In addition to the unique characteristic of the Compounds of the present disclosure, the Compounds of Formula I, wherein Y is —C(H)(OH)— may also be esterified to form physiologically hydrolysable and acceptable ester prodrugs. As used herein, “physiologically hydrolysable and acceptable esters” means esters of Compounds of the present disclosure which are hydrolysable under physiological conditions to yield hydroxy on the one hand and acid, e.g., carboxylic acid on the other, which are themselves physiologically tolerable at doses to be administered. For Example, the Compound of Formula I or Formula II wherein Y is —C(H)(OH) may be esterified to form a prodrug, i.e., a Compound of Formula I Formula II wherein R₁ is —C(O)—C₁₋₂₁ alkyl. In some preferred embodiments, R₁ is —C(O)—C₁₋₂₁ alkyl, e.g., acyl acid esters, e.g., heptanoic, octanoic, decanoic, dodecanoic, tetradecanoic or hexadecanoic acid ester.

Similarly, wherein the Compounds of the present disclosure contain an amine group, prodrug of such amine, e.g., methyl amine prodrugs may also exist wherein the prodrug is cleaved to release the amine metabolite in vivo following administration.

The prodrugs of the Compounds of the present disclosure wherein R₁ is —C(O)—C₁₋₂₁alkyl, preferably —C₆₋₂₁alkyl, more preferably C₆₋₁₅ alkyl, more preferably linear, saturated or unsaturated and optionally substituted with one or more hydroxy or alkoxy groups, are particularly useful for sustained- and/or delayed release so as to achieve a long acting effect, e.g., wherein the Compounds of the present disclosure is released over a period of from about 14 to about 30 to about 180 days, preferably over about 30 or about 60 or about 90 days, for example as described in any of depot composition as described herein. Preferably, the sustained and/or delayed-release formulation is an injectable formulation.

Alternatively, and/or additionally, the Compounds of the present disclosure may be included as a depot formulation, e.g., by dispersing, dissolving or encapsulating the Compounds of the Invention in a polymeric matrix as described in any of Composition 6 and 6.1-6.10, such that the Compound is continually released as the polymer degrades over time. The release of the Compounds of the Invention from the polymeric matrix provides for the controlled- and/or delayed- and/or sustained-release of the Compounds, e.g., from the pharmaceutical depot composition, into a subject, for example a warm-blooded animal such as man, to which the pharmaceutical depot is administered. Thus, the pharmaceutical depot delivers the Compounds of the Invention to the subject at concentrations effective for treatment of the particular disease or medical condition over a sustained period of time, e.g., 14-180 days, preferably about 30, about 60 or about 90 days.

Polymers useful for the polymeric matrix in the Composition of the Invention (e.g., Depot composition of the Invention) may include a polyester of a hydroxyfatty acid and derivatives thereof or other agents such as polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-beta.-hydroxybutyric acid, epsilon.-capro-lactone ring opening polymer, lactic acid-glycolic acid copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethyleneglycol copolymer or polyglycolic acid-polyethyleneglycol copolymer), a polymer of an alkyl alpha-cyanoacrylate (for example poly(butyl 2-cyanoacrylate)), a polyalkylene oxalate (for example polytrimethylene oxalate or polytetramethylene oxalate), a polyortho ester, a polycarbonate (for example polyethylene carbonate or polyethylenepropylene carbonate), a polyortho-carbonate, a polyamino acid (for example poly-gamma.-L-alanine, poly-.gamma.-benzyl-L-glutamic acid or poly-y-methyl-L-glutamic acid), a hyaluronic acid ester, and the like, and one or more of these polymers can be used.

If the polymers are copolymers, they may be any of random, block and/or graft copolymers. When the above alpha-hydroxycarboxylic acids, hydroxydicarboxylic acids and hydroxytricarboxylic acids have optical activity in their molecules, any one of D-isomers, L-isomers and/or DL-isomers may be used. Among others, alpha-hydroxycarboxylic acid polymer (preferably lactic acid-glycolic acid polymer), its ester, poly-alpha-cyanoacrylic acid esters, etc. may be used, and lactic acid-glycolic acid copolymer (also referred to as poly(lactide-alpha-glycolide) or poly(lactic-co-glycolic acid), and hereinafter referred to as PLGA) are preferred. Thus, in one aspect the polymer useful for the polymeric matrix is PLGA. As used herein, the term PLGA includes polymers of lactic acid (also referred to as polylactide, poly(lactic acid), or PLA). Most preferably, the polymer is the biodegradable poly(d,l-lactide-co-glycolide) polymer.

In a preferred embodiment, the polymeric matrix of the invention is a biocompatible and biodegradable polymeric material. The term “biocompatible” is defined as a polymeric material that is not toxic, is not carcinogenic, and does not significantly induce inflammation in body tissues. The matrix material should be biodegradable wherein the polymeric material should degrade by bodily processes to products readily disposable by the body and should not accumulate in the body. The products of the biodegradation should also be biocompatible with the body in that the polymeric matrix is biocompatible with the body. Particular useful examples of polymeric matrix materials include poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes, such as, glycerol mono- and distearate, and the like. The preferred polymer for use in the practice of this invention is dl(polylactide-co-glycolide). It is preferred that the molar ratio of lactide to glycolide in such a copolymer be in the range of from about 75:25 to 50:50.

Useful PLGA polymers may have a weight-average molecular weight of from about 5,000 to 500,000 Daltons, preferably about 150,000 Daltons. Dependent on the rate of degradation to be achieved, different molecular weight of polymers may be used. For a diffusional mechanism of drug release, the polymer should remain intact until all of the drug is released from the polymeric matrix and then degrade. The drug can also be released from the polymeric matrix as the polymeric excipient bioerodes.

The PLGA may be prepared by any conventional method, or may be commercially available. For example, PLGA can be produced by ring-opening polymerization with a suitable catalyst from cyclic lactide, glycolide, etc. (see EP-0058481B2; Effects of polymerization variables on PLGA properties: molecular weight, composition and chain structure).

It is believed that PLGA is biodegradable by means of the degradation of the entire solid polymer composition, due to the break-down of hydrolysable and enzymatically cleavable ester linkages under biological conditions (for example in the presence of water and biological enzymes found in tissues of warm-blooded animals such as humans) to form lactic acid and glycolic acid. Both lactic acid and glycolic acid are water-soluble, non-toxic products of normal metabolism, which may further biodegrade to form carbon dioxide and water. In other words, PLGA is believed to degrade by means of hydrolysis of its ester groups in the presence of water, for example in the body of a warm-blooded animal such as man, to produce lactic acid and glycolic acid and create the acidic microclimate. Lactic and glycolic acid are by-products of various metabolic pathways in the body of a warm-blooded animal such as man under normal physiological conditions and therefore are well tolerated and produce minimal systemic toxicity.

In another embodiment, the polymeric matrix useful for the invention may comprise a star polymer wherein the structure of the polyester is star-shaped. These polyesters have a single polyol residue as a central moiety surrounded by acid residue chains. The polyol moiety may be, e. g., glucose or, e. g., mannitol. These esters are known and described in GB 2,145,422 and in U.S. Pat. No. 5,538,739, the contents of which are incorporated by reference.

The star polymers may be prepared using polyhydroxy compounds, e. g., polyol, e.g., glucose or mannitol as the initiator. The polyol contains at least 3 hydroxy groups and has a molecular weight of up to about 20,000 Daltons, with at least 1, preferably at least 2, e.g., as a mean 3 of the hydroxy groups of the polyol being in the form of ester groups, which contain polylactide or co-polylactide chains. The branched polyesters, e.g., poly (d, l-lactide-co-glycolide) have a central glucose moiety having rays of linear polylactide chains.

The depot compositions of the invention (e.g., Compositions 6 and 6.1-6.10, in a polymer matrix) as hereinbefore described may comprise the polymer in the form of microparticles or nanoparticles, or in a liquid form, with the Compounds of the Invention dispersed or encapsulated therein. “Microparticles” is meant solid particles that contain the Compounds of the Invention either in solution or in solid form wherein such compound is dispersed or dissolved within the polymer that serves as the matrix of the particle. By an appropriate selection of polymeric materials, a microparticle formulation can be made in which the resulting microparticles exhibit both diffusional release and biodegradation release properties.

When the polymer is in the form of microparticles, the microparticles may be prepared using any appropriate method, such as by a solvent evaporation or solvent extraction method. For example, in the solvent evaporation method, the Compounds of the Invention and the polymer may be dissolved in a volatile organic solvent (for example a ketone such as acetone, a halogenated hydrocarbon such as chloroform or methylene chloride, a halogenated aromatic hydrocarbon, a cyclic ether such as dioxane, an ester such as ethyl acetate, a nitrile such as acetonitrile, or an alcohol such as ethanol) and dispersed in an aqueous phase containing a suitable emulsion stabilizer (for example polyvinyl alcohol, PVA). The organic solvent is then evaporated to provide microparticles with the Compounds of the Invention encapsulated therein. In the solvent extraction method, the Compounds of the Invention and polymer may be dissolved in a polar solvent (such as acetonitrile, dichloromethane, methanol, ethyl acetate or methyl formate) and then dispersed in an aqueous phase (such as a water/PVA solution). An emulsion is produced to provide microparticles with the Compounds of the Invention encapsulated therein. Spray drying is an alternative manufacturing technique for preparing the microparticles.

Another method for preparing the microparticles of the invention is also described in both U.S. Pat. Nos. 4,389,330 and 4,530,840.

The microparticle of the present invention can be prepared by any method capable of producing microparticles in a size range acceptable for use in an injectable composition. One preferred method of preparation is that described in U.S. Pat. No. 4,389,330. In this method the active agent is dissolved or dispersed in an appropriate solvent. To the agent-containing medium is added the polymeric matrix material in an amount relative to the active ingredient that provides a product having the desired loading of active agent. Optionally, all of the ingredients of the microparticle product can be blended in the solvent medium together.

Solvents for the Compounds of the Invention and the polymeric matrix material that can be employed in the practice of the present invention include organic solvents, such as acetone; halogenated hydrocarbons, such as chloroform, methylene chloride, and the like; aromatic hydrocarbon compounds; halogenated aromatic hydrocarbon compounds; cyclic ethers; alcohols, such as, benzyl alcohol; ethyl acetate; and the like. In one embodiment, the solvent for use in the practice of the present invention may be a mixture of benzyl alcohol and ethyl acetate. Further information for the preparation of microparticles useful for the invention can be found in U.S. Patent Publication Number 2008/0069885, the contents of which are incorporated herein by reference in their entirety.

The amount of the Compounds of the present disclosure incorporated in the microparticles usually ranges from about 1 wt % to about 90 wt. %, preferably 30 to 50 wt. %, more preferably 35 to 40 wt. %. By weight % is meant parts of the Compounds of the present disclosure per total weight of microparticle.

The pharmaceutical depot compositions may comprise a pharmaceutically-acceptable diluent or carrier, such as a water miscible diluent or carrier.

Details of Osmotic-controlled Release Oral Delivery System composition may be found in EP 1 539 115 (U.S. Pub. No. 2009/0202631) and WO 2000/35419, the contents of each of which are incorporated by reference in their entirety.

A “therapeutically effective amount” is any amount of the Compounds of the invention (for example as contained in the pharmaceutical depot) which, when administered to a subject suffering from a disease or disorder, is effective to cause a reduction, remission, or regression of the disease or disorder over the period of time as intended for the treatment.

Dosages employed in practicing the present invention will of course vary depending, e.g. on the particular disease or condition to be treated, the particular Compound of the Invention used, the mode of administration, and the therapy desired. Unless otherwise indicated, an amount of the Compound of the Invention for administration (whether administered as a free base or as a salt form) refers to or is based on the amount of the Compound of the Invention in free base form (i.e., the calculation of the amount is based on the free base amount).

Compounds of the Invention may be administered by any satisfactory route, including orally, parenterally (intravenously, intramuscular or subcutaneous) or transdermally, but are preferably administered orally. In certain embodiments, the Compounds of the Invention, e.g., in depot formulation, are preferably administered parenterally, e.g., by injection.

In general, satisfactory results for Method 1 and 1.1-1.55, Method 2 and 2.1-2.20, and Method 3 and 3.1-3.40, or use of the Compounds of the present disclosure as hereinbefore described, e.g. for the treatment of a combination of diseases such as a combination of at least depression, psychosis, e.g., (1) psychosis, e.g., schizophrenia, in a patient suffering from depression; (2) depression in a patient suffering from psychosis, e.g., schizophrenia; (3) mood disorders associated with psychosis, e.g., schizophrenia, or Parkinson's disease; (4) sleep disorders associated with psychosis, e.g., schizophrenia, or Parkinson's disease; and (5) substance addiction, substance use disorders and/or substance-induced disorders, as set forth above are indicated to be obtained on oral administration at dosages of the order from about 1 mg to 100 mg once daily, preferably 2.5 mg-50 mg, e.g., 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg or 50 mg, once daily, preferably via oral administration.

Satisfactory results for Method 2 or 2.1-2.20 or use of the Compounds of the present disclosure as hereinbefore described, e.g. for the treatment of sleep disorder alone are indicated to be obtained on oral administration at dosages of the order from about 2.5 mg-5 mg, e.g., 2.5 mg, 3 mg, 4 mg or 5 mg, of a Compound of the Invention, in free or pharmaceutically acceptable salt form, once daily, preferably via oral administration.

Satisfactory results for Method I-A or Method II-A, or any of 3.1-3.40 are indicated to be obtained at less than 100 mg, preferably less than 50 mg, e.g., less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg, less than 5 mg, less than 2.5 mg, once daily. Satisfactory results for Method II-A or any of 3.1-3.41 are indicated to be obtained at less than 5 mg, preferably less than 2.5 mg.

For treatment of the disorders disclosed herein wherein the depot composition is used to achieve longer duration of action, the dosages will be higher relative to the shorter action composition, e.g., higher than 1-100 mg, e.g., 25 mg, 50 mg, 100 mg, 500 mg, 1,000 mg, or greater than 1000 mg. Duration of action of the Compounds of the present disclosure may be controlled by manipulation of the polymer composition, i.e., the polymer:drug ratio and microparticle size. Wherein the composition of the invention is a depot composition, administration by injection is preferred.

The pharmaceutically acceptable salts of the Compounds of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Further details for the preparation of these salts, e.g., toluenesulfonic salt in amorphous or crystal form, may be found in PCT/US08/03340 and/or U.S. Provisional Appl. No. 61/036,069 (each equivalent to US 2011/112105).

Pharmaceutical compositions comprising Compounds of the present disclosure may be prepared using conventional diluents or excipients (an example include, but is not limited to sesame oil) and techniques known in the galenic art. Thus, oral dosage forms may include tablets, capsules, solutions, suspensions and the like.

The term “concurrently” when referring to a therapeutic use means administration of two or more active ingredients to a patient as part of a regimen for the treatment of a disease or disorder, whether the two or more active agents are given at the same or different times or whether given by the same or different routes of administrations. Concurrent administration of the two or more active ingredients may be at different times on the same day, or on different dates or at different frequencies.

The term “simultaneously” when referring to a therapeutic use means administration of two or more active ingredients at or about the same time by the same route of administration.

The term “separately” when referring to a therapeutic use means administration of two or more active ingredients at or about the same time by different route of administration

Methods of Making the Compounds of the Invention:

The Compounds of the present disclosure wherein X is —NH— or —N(CH₃)— and Y is —C(═O) may be prepared by reacting (6bR, 10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline or its 1-methyl analog with 4-chloro-4′-fluorobutyrophenone, in accordance with Scheme 1 below:

Compounds of the present disclosure wherein X is —NH— or —N(CH₃)— and Y is —CH(OH)— may be prepared by reacting the 4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one produced in Scheme 1 (or its 1-methyl analog) with a reducing agent, in accordance with Scheme 2, below:

The reducing agent may be a metal hydride, e.g., sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, aluminum hydride, diisobutylaluminum hydride, preferably sodium borohydride. Further reagents for reduction of ketones may be found in Jerry March, Advanced Organic Chemistry, Reactions Mechanisms and Structures, p. 910-911, (1992, John Wiley & Sons, Inc.), Fourth Edition, the contents of which are incorporated by reference.

Isolation or purification of the diastereomers of the Compounds of the Invention may be achieved by conventional methods known in the art, e.g., column purification, preparative thin layer chromatography, preparative HPLC, crystallization, trituration, simulated moving beds and the like.

The Compounds of Formula I wherein Y is —CH(O—R₁)— and R₁ is other than H can be prepared by several commonly used esterification methods such as alcoholysis of acyl halides, anhydrides or active esters. For example, The Compound of Formula I, wherein R₁ is —C(O)— alkyl may be prepared by reacting:

-   -   (a) L-C(O)—C₁₋₂₁ alkyl, wherein L is a leaving group such as a         halo group (for example, chloro or bromo),         trifluoromethylsulfonyloxy (—OSO₂CF₃), tosyloxy         (—O—S(O)₂—C₆H₄—CH₃), methylsulfonyloxy (—O—S(O)₂—CH₃),         1H-benzo[d][1,2,3]triazol-1-yloxy or succinimidyloxy group,     -   with     -   (b) the Compound of Formula I wherein Y is —C(H)(OH),         preferably in the presence of a base (e.g., diisopropylamine,         triethyl amine or pyridine). For example L-C(O)—C₁₋₂₁ alkyl is         an acetyl halide, decanoyl halide or heptanoyl halide, which may         be prepared by reacting HO—C(O)—C₁₋₂₁ alkyl, e.g., with thionyl         chloride, P(X′)₃ or P(X′)₅ wherein X′ is Cl or Br. Wherein L is         tosyloxy-C(O)—C₁₋₂₁ alkyl or methylsulfonyloxy-C(O)—C₁₋₂₁alkyl,         these compounds may be prepared by reacting HO—C(O)—C₁₋₂₁ alkyl         with tosyl-chloride or mesyl-chloride, preferably in the         presence of a base such as pyridine. Synthesis of the Compound         of Formula II-A where R₁ is other than H may be summarized in         Scheme 3 below:

Alternatively, the synthesis of the compound of Formula II-A where R₁ is other than H maybe achieved by reacting HO—C(O)—C₁₋₂₁alkyl with (i) a compound of Formula I wherein Y is —C(H)(OH) in the presence of a base such as DIEPA and NEt₃, and (ii) a dehydrating or coupling reagent such as 2-fluoro-1-ethyl pyridinium tetrafluoroborate (FEP), tetramethylfluoroamidinium hexafluorophosphate (TFFH) or 1,1,3,3-bis(tetramethylene) chlorouronium hexafluorophosphate (PyClU).

Salts of the Compounds of the present disclosure may be prepared as similarly described in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; U.S. RE39680; U.S. RE39679; and WO 2009/114181 (US 2011/112105), the contents of each of which are incorporated by reference in their entirety.

Diastereomers of prepared compounds can be separated by, for example, HPLC using CHIRALPAK® AY-H, 5μ, 30×250 mm at room temperature and eluted with 10% ethanol/90% hexane/0.1% dimethylethylamine. Peaks can be detected at 230 nm to produce 98-99.9% ee of the diastereomer.

Example 1: Synthesis of 4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one

(6bR, 10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylic acid ethyl ester (6.4 g, 21.2 mmol) is suspended in HBr acetic acid solution (64 mL, 33% w/w) at room temperature. The mixture is heated at 50° C. for 16 h. After cooling, and treatment with ethyl acetate (300 mL), the mixture is filtered. The filter cake is washed with ethyl acetate (300 mL), and then dried under vacuum. The obtained HBr salt is then suspended in methanol (200 mL), and cooled with dry ice in isopropanol. Under vigorous stirring, ammonia solution (10 mL, 7N in methanol) is added slowly to the suspension to adjust the pH of the mixture to 10. The obtained mixture is dried under vacuum without further purification to give crude (6bR, 10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline (8.0 g), which is used directly in the next step. MS (ESI) m/z 230.2 [M+H]⁺.

The crude (6bR, 10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline (1.4 g) is dissolved in DMF (14 mL), and then KI (2.15 g) and 4-Chloro-4′-fluorobutyrophenone (2 mL) are added successively. The mixture is degassed with argon, followed by adding N,N-diisopropylethylamine (DIPEA, 2 mL). The mixture is heated at 78° C. for 2 h. After cooling, the solvents are removed under reduced pressure. The dark brown residue is suspended in dichloromethane (100 mL) and then extracted with water (30 mL). The organic layer is separated, and dried over K₂CO₃. After filtration, the solvents are removed under reduced pressure. The obtained crude product is purified by silica gel column chromatography eluting with 0-10% of methanol in ethyl acetate containing 0.1% of 7N ammonia in methanol to yield 4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one as a light yellow solid (767 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 10.3 (s, 1H), 8.1-8.0 (m, 2H), 7.3 (dd, J=8.86 Hz, 2H), 6.8 (d, J=7.25 Hz, 1H), 6.6 (dd, J=7.55 Hz, 1H), 6.6 (d, J=7.74 Hz, 1H), 3.8 (d, J=14.49 Hz, 1H), 3.3-3.3 (m, 1H), 3.2-3.2 (m, 1H), 3.1-3.0 (m, 1H), 3.0 (t, J=6.88 Hz, 2H), 2.8-2.8 (m, 1H), 2.6-2.5 (m, 1H), 2.3-2.2 (m, 2H), 2.1-2.0 (m, 1H), 1.9-1.8 (m, 1H), 1.8 (t, J=6.99 Hz, 2H), 1.6 (t, J=11.25 Hz, 2H). MS (ESI) m/z 394.2 [M+H]+.

Example 2: Synthesis of 4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-ol

4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one (50 mg, 0.127 mmol) is dissolved in methanol (5 mL). Under stirring, NaBH₄ (31 mg, 0.82 mmol) is added in batches. After the completion of the addition, the mixture is stirred at room temperature for 30 min. Methanol is evaporated under reduced pressure. The residue is dissolved in dichloromethane (10 mL) and then extracted with water (2×0.5 mL). The combined organic phase is dried over K₂CO₃. After filtration, the filtrate is concentrated under reduced pressure and then further dried under vacuum to give 4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-ol as a pale yellow foamy solid (45 mg, yield 90%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.3 (s, 1H), 7.4-7.3 (m, 2H), 7.2-7.1 (m, 2H), 6.7 (d, J=7.29 Hz, 1H), 6.7-6.6 (m, 1H), 6.6 (d, J=7.74 Hz, 1H), 5.4 (s, 1H), 4.7-4.4 (m, 1H), 3.8 (d, J=14.49 Hz, 1H), 3.3-3.3 (m, 1H), 3.3-3.2 (m, 1H), 3.2-3.1 (m, 1H), 2.8-2.7 (m, 1H), 2.6-2.5 (m, 1H), 2.3-2.1 (m, 2H), 2.1-2.0 (m, 1H), 2.0-1.9 (m, 1H), 1.8-1.7 (m, 1H), 1.7-1.5 (m, 3H), 1.5-1.4 (m, 1H), 1.4-1.3 (m, 1H). MS (ESI) m/z 396.2 [M+H]⁺.

Example 3: Synthesis of (6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

A mixture of (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (100 mg, 0.436 mmol), 1-(3-chloroproxy)-4-fluorobenzene (100 μL, 0.65 mmol) and KI (144 mg, 0.87 mmol) in DMF (2 mL) is degassed with argon for 3 minutes and DIPEA (150 μL, 0.87 mmol) is added. The resulting mixture is heated to 78° C. and stirred at this temperature for 2 h. The mixture is cooled to room temperature and then filtered. The filter cake is purified by silica gel column chromatography using a gradient of 0-100% ethyl acetate in a mixture of methanol/7N NH₃ in methanol (1:0.1 v/v) as an eluent to produce partially purified product, which is further purified with a semi-preparative HPLC system using a gradient of 0-60% acetonitrile in water containing 0.1% formic acid over 16 min to obtain the title product as a solid (50 mg, yield 30%). MS (ESI) m/z 406.2 [M+1]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 10.3 (s, 1H), 7.2-7.1 (m, 2H), 7.0-6.9 (m, 2H), 6.8 (dd, J=1.03, 7.25 Hz, 1H), 6.6 (t, J=7.55 Hz, 1H), 6.6 (dd, J=1.07, 7.79 Hz, 1H), 4.0 (t, J=6.35 Hz, 2H), 3.8 (d, J=14.74 Hz, 1H), 3.3-3.2 (m, 3H), 2.9 (dd, J=6.35, 11.13 Hz, 1H), 2.7-2.6 (m, 1H), 2.5-2.3 (m, 2H), 2.1 (t, J=11.66 Hz, 1H), 2.0 (d, J=14.50 Hz, 1H), 1.9-1.8 (m, 3H), 1.7 (t, J=11.04 Hz, 1H).

Example 4: Cellular and Nuclear Receptor Functional Assays

Cellular and Nuclear Receptor Functional Assays are performed on the compounds of Formula II-B and II-C (Examples 1 and 2, respectively) according to the procedure of Wang, J. B. et al. (1994), FEBS Lett., 338:217-222. The compounds are tested at several concentrations to determine their IC₅₀ or EC₅₀. Cellular agonist effects are calculated as percent of control response to a known reference agonist for each target and cellular antagonist effect is calculated as a percent inhibition of control reference agonist response for each target.

The following assay is performed to determine the effect of the Compound of Formula II-B on the μ (MOP) (h) receptor:

Assay Measured Detection (Receptor) Source Stimulus Incubation Component Method μ (MOP) (h) human none 10 min @ cAMP HTRF (agonist effect) recombinant (0.3 μM 37° C. MOP receptor DAMGO (CHO cells) for control) μ (MOP) (h) human DAMGO 10 min @ cAMP HTRF (antagonist recombinant (20 nM) 37° C. effect) MOP receptor (CHO cells)

For the antagonists, the apparent dissociation constants (K_(B)) are calculated using the modified Cheng Prusoff equation:

$K_{B} = \frac{IC_{50}}{1 + \left( {{A/E}C_{50A}} \right)}$ where A=concentration of reference agonist in the assay, and EC_(50A)=EC₅₀ value of the reference agonist.

The compound of Formula II-B is found to have a μ (MOP) (h) (antagonist effect) with an IC₅₀ of 1.3×10⁻⁶M; and a K_(B) of 1.4×10⁻⁷M; and the compound of Formula II-C is found to have an IC₅₀ greater than 1×10⁻⁵, which was the highest concentration tested.

The agonist activity results are expressed as a percent of control agonist response:

$\frac{{measured}\mspace{14mu}{response}}{{control}\mspace{14mu}{response}} \times 100$ and antagonist activity as a percent inhibition of control agonist maximum response:

$100 - \left( {\frac{{measured}\mspace{14mu}{response}}{{control}\mspace{14mu}{response}} \times 100} \right)$ obtained in the presence of the Compound of Formula II-B or II-C.

The EC₅₀ values (concentration producing a half-maximal response) and IC₅O values (concentration causing a half-maximal inhibition of the control agonist response) are determined by non-linear regression analysis of the concentration-response curves generated with mean replicate values using Hill equation curve fitting:

$Y = {D + \left\lbrack \frac{A - D}{1 + \left( {C/C_{50}} \right)^{nH}} \right\rbrack}$ where Y=response, A=left asymptote of the curve, D=right asymptote of the curve, C=compound concentration, and C₅₀=EC₅₀ or IC₅₀, and nH=slope factor. The analysis is performed using software developed in-house and validated by comparison with data generated by the commercial software SigmaPlot® 4.0 for Windows® (© 1997 by SPSS Inc.).

Example 5: Receptor Binding Profile of Compound of Formulas II-B, II-C and Ex. 3

Receptor binding is determined for the Compounds of Formulas II-B and II-C using the tosylate salt of the compound of Formula A as a control. The following literature procedures are used, each of which reference is incorporated herein by reference in their entireties: 5-HT_(2A): Bryant, H. U. et al. (1996), Life Sci., 15:1259-1268; D₂: Hall, D. A. and Strange, P. G. (1997), Brit. J. Pharmacol., 121:731-736; D1: Zhou, Q. Y. et al. (1990), Nature, 347:76-80; SERT: Park, Y. M. et al. (1999), Anal. Biochem., 269:94-104; Mu opiate receptor: Wang, J. B. et al. (1994), FEBS Lett., 338:217-222.

In general, the results are expressed as a percent of control specific binding:

$\frac{{me}\;{asured}\mspace{14mu}{specific}\mspace{14mu}{binding}}{{control}\mspace{14mu}{specific}\mspace{14mu}{binding}} \times 100$ and as a percent inhibition of control specific binding:

$100 - \left( {\frac{{me}\;{asured}\mspace{14mu}{specific}\mspace{14mu}{binding}}{{control}\mspace{14mu}{specific}\mspace{14mu}{binding}} \times 100} \right)$ obtained in the presence of the test compounds.

The IC₅₀ values (concentration causing a half-maximal inhibition of control specific binding) and Hill coefficients (nH) are determined by non-linear regression analysis of the competition curves generated with mean replicate values using Hill equation curve fitting:

$Y = {D + \left\lbrack \frac{A - D}{1 + \left( {C/C_{50}} \right)^{nH}} \right\rbrack}$ where Y=specific binding, A=left asymptote of the curve, D=right asymptote of the curve, C=compound concentration, C₅₀=IC₅₀, and nH=slope factor. This analysis was performed using in-house software and validated by comparison with data generated by the commercial software SigmaPlot® 4.0 for Windows® (© 1997 by SPSS Inc.). The inhibition constants (Ki) were calculated using the Cheng Prusoff equation:

${Ki} = \frac{IC_{50}}{\left( {1 + {L/K_{D}}} \right)}$ where L=concentration of radioligand in the assay, and K_(D)=affinity of the radioligand for the receptor. A Scatchard plot is used to determine the K_(D).

The following receptor affinity results are obtained, using the tosylate salt of a Compound of Formula A as a control:

Formula A Formula II-B Formula II-C (tosylate (Ex. 1) (Ex. 2) Example 3 salt) Receptor Ki (nM) or maximum inhibition 5-HT_(2A) 11 31% inhibition 8.3 10 at 240 nM D2 47% inhibition 11% inhibition 160 49 at 240 nM at 240 nM D1 22 13% inhibition 50 41 at 100 nM SERT 44% inhibition No inhibition 590 16 at 240 nM seen Mu opiate 22 85 11 >10,000 receptor Delta No opioid inhibition Kappa 16% @ opioid 100 nM NOP No (Nociceptin inhibition Receptor)

Example 6: DOI-Induced Head Twitch Model in Mice

R-(−)-2,5-dimethoxy-4-iodoamphetamine (DOI) is an agonist of the serotonin 5-HT₂ receptor family. When administered to mice, it produces a behavioral profile associated with frequent head twitches. The frequency of these head twitches during a predetermined period of time can be taken as an estimate of 5-HT₂ receptor agonism in the brain. Conversely, this behavioral assay can be used to determine 5-HT₂ receptor antagonism in the brain by administering the DOI with or without an antagonist and recording the reduction in DOI-induced head twitches after the administration of the antagonist.

The method of Darmani et al., Pharmacol Biochem Behav. (1990) 36:901-906 (the contents of which are incorporated by reference in their entirety) is used with some modifications. (±)-DOI HCl is injected subcutaneously and the mice are immediately placed in a conventional plastic cage. The number of head twitches is counted during 6 min, beginning 1 min after DOI administration. The tested compound is administered orally 0.5 hr before the injection of DOI. Results area calculated as the EC50 for reducing DOI-induced head twitches. The results are shown in the following Table:

Compound EC₅₀ (mg/kg, p.o.) Example 1 (Formula II-B) 0.23 Example 2 (Formula II-C) 2.03 Example 3 0.44 Formula A 0.09 Formula B 0.31 The results show that the compounds of Example 1 and 3 potently block DOI head twitch, comparable to the reference compounds Formula A and C, and consistent with the in-vitro 5-HT_(2A) results shown in Example 5. In contrast, the compound of Example 2 is relatively inactive in this functional assay, confirming that this compound is relatively weaker in its serotonin receptor antagonism than other structurally similar compounds.

Example 7: Mouse Tail Flick Assays

The Mouse Tail Flick Assay is a measure of analgesia, indicated by the pain reflex threshold of restrained mice. Male CD-1 mice are positioned with their tails under a focused beam of a high-intensity infrared heat source, resulting in heating of the tail. The animal can withdraw its tail from the heat source at any time that it becomes uncomfortable. The amount of time (latency) between turning on the heating instrument and the flicking of the mouse's tail out of path of the heat source is recorded. Administration of morphine results in analgesia, and this produces a delay in the mouse's reaction to the heat (increased latency). Prior administration of a morphine (MOR) antagonist, i.e., naloxone (NAL), reverses the effect and results in normal latency time. This test is used as a functional assay to gauge antagonism of mu-opiate receptors.

Example 7a: Antagonism of Morphine-Induced Analgesia by Compounds of Examples 1 and 3

Ten male CD-1 mice (about 8 weeks of age) are assigned to each of five treatment groups. The groups are treated as follows: Group (1) [negative control]: administered 0.25% methylcellulose vehicle p.o., 60 minutes before the tail flick test, and saline vehicle 30 minutes before the tail flick test; Group (2) [positive control]: administered 0.25% methylcellulose vehicle p.o., 60 minutes before the test, and 5 mg/kg morphine in saline 30 minutes before the test; Group (3) [positive control]: administered 3 mg/kg naloxone in saline 50 minutes before the test, and 5 mg/kg morphine in saline 30 minutes before the test; Groups (4)-(6): administered either 0.1 mg/kg, 0.3 mg/kg or 1 mg/kg of the test compound in 0.25% methylcellulose vehicle p.o., 60 minutes before the test, and 5 mg/kg morphine in 30 minutes before the test. The experiment is repeated for the compounds of Example 1 and Example 3. The results are shown in the following table as mean latency measured in seconds:

Group 4 Group 5 Group 6 Cmpd/ Cmpd/ Cmpd/ Mor Mor Mor Group 1 Group 2 Group 3 (0.1 mg/ (0.3 mg/ (1 mg/ Veh/Veh Veh/Mor Nal/Mor kg) kg) kg) Ex. 1 1.028 9.361 2.496 8.870 6.907 6.240 Ex. 3 0.887 8.261 3.013 6.947 5.853 6.537

The results demonstrate that the compounds of Example 1 and Example 3 both exert a dose-dependent blockade of morphine-induced mu-opiate receptor activity.

Example 7b: Analgesia by Compound of Example 3, Inhibited by Naloxone

In a second study using the mouse tail flick assay as described above, the compound of Example 3 is further compared at doses of 1.0 mg/kg, 3.0 mg/kg and 10 mg/kg against morphine at 5 mg/kg with and without pre-dosing with naloxone at 3 mg/kg (intraperitoneal). In the pre-treatment groups, the naloxone is administered 20 minutes prior to the tail flick test. In the non-pre-treatment controls, saline is administered 20 minutes prior to the tail flick test. In each group, the vehicle, morphine or compound of Example 3 is administered 30 minutes before the tail flick test. The results are shown in the table below as mean latency in seconds:

Ex. 3 at Ex. 3 at Ex. 3 at Vehicle Morphine 1 mg/kg 3 mg/kg 10 mg/kg Saline 0.9 9.8 4.1 7.4 9.8 pre-treatment Naloxone 0.8 1.5 1.3 1.7 2.1 pre-treatment

It is found that administration of the compound of Example 3 at all doses significantly increased the latency to tail flick, and that this effect is attenuated by pre-treatment with naloxone. This result demonstrates a dose-dependent analgesic effect produced by the Compound of Example 3, and further suggests that this effect is mediated by mu-opioid receptor agonism.

Example 7c: Time Course for Analgesia, Compound of Example 3

The tail flick assay as described above is repeated to determine the time course of analgesia resulting from administration of the compound of Example 3. Mice are administered s.c. either (1) vehicle 30 minutes prior to assay, (2) 5 mg/kg morphine 30 minutes prior to assay, or (3)-(7) the 1 mg/kg of compound of Example 3 30 minutes, 2 hours, 4 hours, 8 hours or 24 hours prior to assay. The results are shown in the table below as mean latency in seconds:

Treatment TF Latency (s) Vehicle, 30 min prior 1.30 Morphine, 30 min prior 7.90 Cmpd. Ex. 3, 30 min prior 5.77 Cmpd. Ex. 3, 2 h prior 2.42 Cmpd. Ex. 3, 4 h prior 1.48 Cmpd. Ex. 3, 6 h prior 1.36 Cmpd. Ex. 3, 24 h prior 1.29

The results show that the Compound of Example 3 produces effective analgesia when administered 30 minutes or 2 hours prior to the tail flick assay (ANOVA, P<0.001 vs. vehicle). When administered 4 hours, 8 hours, or 24 hours prior to the tail flick assay, the compound of Example 3 at 1 mg/kg does not produce an analgesic effect significantly different from the vehicle control. Thus, the compound of Example 3 does not produce prolonged analgesia, which means that it would have a lower potential for abuse and a lower risk of drug-drug interactions compared to other opiate analgesics.

Example 7d: Analgesia from Chronic Administration of the Compound of Example 3

The tail flick assay described above is repeated using a test model in which animals receive a 14-day chronic treatment regimen, followed by an acute treatment 30 minutes prior to the tail flick assay. The mice are divided into three broad groups with six sub-groups of 10 mice each. The three groups receive as the chronic treatment either (A) vehicle, (B) compound of Example 3 at 0.3 mg/kg, or (C) compound of Example 3 at 3.0 mg/kg. Each sub-group further receives as the acute treatment either (1) vehicle, or (2)-(6) the compound of Example 3 at 0.01, 0.03, 0.1, 0.3 or 1.0 mg/kg. All treatments are administered s.c. The results are shown in the table below as mean latency to tail flick in seconds:

Group Chronic Treatment Acute Treatment Latency (s) (A) Vehicle Vehicle 1.09 Vehicle Ex. 3, 0.01 mg/kg 1.87 Vehicle Ex. 3, 0.03 mg/kg 2.50 Vehicle Ex. 3, 0.1 mg/kg 5.26 Vehicle Ex. 3, 0.3 mg/kg 8.26 Vehicle Ex. 3, 1.0 mg/kg 9.74 (B) Ex. 3, 0.3 mg/kg Vehicle 0.893 Ex. 3, 0.3 mg/kg Ex. 3, 0.01 mg/kg 1.66 Ex. 3, 0.3 mg/kg Ex. 3, 0.03 mg/kg 1.30 Ex. 3, 0.3 mg/kg Ex. 3, 0.1 mg/kg 2.60 Ex. 3, 0.3 mg/kg Ex. 3, 0.3 mg/kg 3.93 Ex. 3, 0.3 mg/kg Ex. 3, 1.0 mg/kg 5.64 (C) Ex. 3, 3.0 mg/kg Vehicle 1.04 Ex. 3, 3.0 mg/kg Ex. 3, 0.01 mg/kg 1.64 Ex. 3, 3.0 mg/kg Ex. 3, 0.03 mg/kg 1.80 Ex. 3, 3.0 mg/kg Ex. 3, 0.1 mg/kg 3.94 Ex. 3, 3.0 mg/kg Ex. 3, 0.3 mg/kg 4.84 Ex. 3, 3.0 mg/kg Ex. 3, 1.0 mg/kg 7.94

It is found that 0.1, 0.3 and 1.0 mg/kg acute treatment with the compound of Example 3 produces a statistically significant dose-dependent analgesic effect compared to in-group acute treatment with vehicle. This is true for each of the chronic groups (A), (B) and (C). As compared to pre-treatment with vehicle, pre-treatment with the compound of Example 3 at 0.3 mg/kg or 3.0 mg/kg generally showed a statistically significant decrease in tail flick latency when the same acute treatment subgroups are compared. These results demonstrate that while some tolerance to the analgesic effect of the compound of Example 3 occurs after 14-days of chronic treatment, the analgesia obtained remains effective despite chronic pre-treatment.

Example 8: CNS Phosphoprotein Profile

A comprehensive molecular phosphorylation study is also carried out to examine the central nervous system (CNS) profile of the compounds of Example 1 and Example 3. The extent of protein phosphorylation for selected key central nervous system proteins is measured in mice nucleus accumbens. Examined proteins include ERK1, ERK2, Glu1, NR2B and TH (tyrosine hydroxylase), and the compounds of Example 1 and 3 were compared to the antipsychotic agents risperidone and haloperidol.

Mice were treated with the compound of Example 1 or 3 at 3 mg/kg, or with haloperidol at 2 mg/kg. Mice were killed 30 minutes to 2 hours post-injection by focused microwave cranial irradiation, which preserves brain phosphoprotein as it exists at the time of death. The nucleus accumbens was then dissected from each mouse brain, sliced and frozen in liquid nitrogen. Samples were further prepared for phosphoprotein analysis via SDS-PAGE electrophoresis followed by phosphoprotein-specific immunoblotting, as described in Zhu H, et al., Brain Res. 2010 Jun. 25; 1342:11-23. Phosphorylation at each site was quantified, normalized to total levels of the protein (non-phosphorylated), and expressed as percent of the level of phosphorylation in vehicle-treated control mice.

The results demonstrate that neither the compound of Example 1 nor of Example 3 has a significant effect on tyrosine hydroxylase phosphorylation at Ser40 at 30 minutes or 60 minutes, in contrast to haloperidol which produces a greater than 400% increase, and risperidone which produces a greater than 500% increase, in TH phosphorylation. This demonstrates that inventive compounds do not disrupt dopamine metabolism.

The results further demonstrate that neither the compound of Example 1 nor of Example 3 has a significant effect on NR2B phosphorylation at Tyr1472 at 30-60 minutes. The compounds produce a slight increase in GluR1 phosphorylation at Ser845, and a slight decrease in ERK2 phosphorylation at Thr183 and Tyr185. Protein phosphorylation at various sites in particular proteins are known to be linked to various activities of the cell such as protein trafficking, ion channel activity, strength of synaptic signaling and changes in gene expression. Phosphorylation the Tyr1472 in the NMDA glutamate receptor has been shown to be essential for the maintenance of neuropathic pain. Phosphorylation of Ser845 of the GluR1 AMPA type glutamate receptor is associated with several aspects of strengthening synaptic transmission and enhanced synaptic localization of the receptor to support long term potentiation associated with cognitive abilities. It has also been reported that phosphorylation of this residue results in an increased probability of channel opening. Phosphorylation of ERK2 kinase, a member of the MAP kinase cascade, at residues T183 and Y185 is required for full activation of this kinase, ERK2 is involved in numerous aspects of cell physiology including cell growth, survival and regulation of transcription. This kinase has been reported to be important in synaptogenesis and cognitive function.

Example 9: Mouse Marble-Burying Study (OCD Model)

The marble burying test is used to measure repetitive and anxiety-related behavior in rodents. It is based on the observation that rats and mice will bury either harmful or harmless objects in their bedding, and it has been used as an animal model to measure the effect of pharmacological interventions in treatment of repetitive behavior disorders, such as OCD.

Mice are first divided up into four treatment groups: (1) vehicle negative control, (2) 0.3 mg/kg compound of Example 3, (3) 1.5 mg/kg compound of Example 3, and (4) 20 mg/kg MPEP (2-methyl-6-(phenylethynyl)pyridine) positive control. MPEP is a selective mGluR5 glutamate receptor antagonist. Mice in groups (2) and (3) are orally administered the compound of Example 3 at the stated dosage in a 0.5% methylcellulose aqueous vehicle 30 minutes prior to the test. Mice in groups (1) are orally administered the vehicle, and mice in group (4) are given an intraperitoneal injection of MPEP just prior to the start of the test.

The test is conducted in rectangular cages with 4-5 cm of wood chip bedding in a room with the window shades lowered and the door closed to minimize distractions. Fifteen clean marbles are evenly spaced on top of the bedding in three rows of five marbles. One mouse is placed in each cage. The mouse and cage is left undisturbed for 30 minutes. At the end of the test, the mouse is removed and the number of marbles buried to at least ⅔ of their depth is counted. The results are shown in the following table:

Group Marbles Buried (1) Vehicle 13.2 (2) 0.3 mg/kg Ex. 3 9.3 (3) 1.5 mg/kg Ex. 3 4.7 (4) MPEP 0.2

The results demonstrate that compared to the control, there is a statistically significant decrease in marble burying for the mice treated with 0.3 mg/kg of the compound of Example 3 (p<0.01) and with 1.5 mg/kg of the compound of Example 3 (p<0.001). In addition, there is a clear dose-response relationship evident. The results support the potential utility of Example 3 in OCD therapeutic indications.

Example 10: Mu-Opiate Receptor Activity Assays

The compounds of Example 1 and 3 are tested in CHO-K1 cells expressing hOP3 (human mu-opiate receptor μ1 subtype) using an HTRF-based cAMP assay kit (cAMP Dynamic2 Assay Kit, from Cisbio, #62AM4PEB). Frozen cells are thawed in a 37° C. water bath and are resuspended in 10 mL of Ham's F-12 medium containing 10% FBS. Cells are recovered by centrifugation and resuspended in assay buffer (5 nM KCl, 1.25 mM MgSO₄, 124 mM NaCl, 25 mM HEPES, 13.3 mM glucose, 1.25 mM KH₂PO₄, 1.45 mM CaCl₂), 0.5 g/L protease-free BSA, supplemented with 1 mM IBMX). Buprenorphine, a mu-opiate receptor partial agonist, and naloxone, a mu-opiate receptor antagonist, and DAMGO, a synthetic opioid peptide full agonist, are run as controls.

For agonist assays, 12 μL of cell suspension (2500 cells/well) are mixed with 6 μL forksolin (10 μM final assay concentration), and 6 μL of the test compound at increasing concentrations are combined in the wells of a 384-well white plate and the plate is incubated for 30 minutes at room temperature. After addition of lysis buffer and one hour of further incubation, cAMP concentrations are measured according to the kit instructions. All assay points are determined in triplicate. Curve fitting is performed using XLfit software (IDBS) and EC₅₀ values are determined using a 4-parameter logistic fit. The agonist assay measures the ability of the test compound to inhibit forskolin-stimulated cAMP accumulation.

For antagonist assays, 12 μL of cell suspension (2500 cells/well) are mixed with 6 μL of the test compound at increasing concentrations, and combined in the wells of a 384-well white plate and the plate is incubated for 10 minutes at room temperature. 6 μL of a mixture of DAMGO (D-Ala²-N-MePhe⁴-Gly-ol-enkephelin, 10 nM final assay concentration) and forksolin (10 μM final assay concentration) are added, and the plates are incubated for 30 minutes at room temperature. After addition of lysis buffer, and one hour of further incubation, cAMP concentrations are measured according the kit instructions. All assay points are determined in triplicate. Curve fitting is performed using XLfit software (IDBS) and IC₅₀ values are determined using a 4-parameter logistic fit. Apparent dissociation constants (K_(B)) are calculated using the modified Cheng-Prusoff equation. The antagonist assay measures the ability of the test compound to reverse the inhibition of forskolin-induced cAMP accumulation caused by DAMGO.

The results are shown in FIGS. 1 and 2, and in the Table below. The results demonstrate that the compound of Example 3 is a weak antagonist of the Mu receptor, showing much higher IC₅₀ compared to naloxone, and that it is a moderately high affinity, but partial agonist, showing only about 22% agonist activity relative to DAMGO (as compared to about 79% activity for buprenorphine relative to DAMGO). The compound of Example 1 is also shown to have moderately strong partial agonist activity.

Compound Antagonist IC₅₀ (nM) Agonist EC₅₀ (nM) K_(B) (nM) Naloxone 5.80 — 0.65 DAMGO — 1.56 — Buprenorphine — 0.95 — Cmpd. Ex. 3 641 64.5 71.4  Cmpd Ex. 1 — 140 —

Buprenorphine is a drug used for chronic pain treatment and for opiate withdrawal, but it suffers from the problem that users can become addicted due to its high partial agonist activity. To offset this, the commercial combination of buprenorphine with naloxone is used (sold as Suboxone). Without being bound by theory, it is believed that the compounds of the present invention, which are weaker partial Mu agonists than buprenorphine, with some moderate antagonistic activity, will allow a patient to be more effectively treated for pain and/or opiate withdrawal with lower risks of addiction.

In additional related study using a recombinant human MOP-beta-arresting signaling pathway, it is found that the Compound of Example 3 does not stimulate beta-arrestin signaling via the MOP receptor at concentrations up to 10 μM, but that it is an antagonist with an IC₅₀ of 0.189 μM. In contrast, the full opioid agonist Met-enkephalin stimulates beta-arrestin signaling with an EC₅₀ of 0.08 μM.

Example 11: Rat Tolerance/Dependence Study

The compound of Example 3 is assessed during repeated (28 day) daily subcutaneous administration to male Sprague-Dawley rats to monitor drug effects on dosing and to determine if pharmacological tolerance occurs. In addition, behavioral, physical and physiological signs in the rats is monitored following abrupt cessation of repeated dosing to determine whether the compound induces physical dependence on withdrawal. Further, a pharmacokinetic study is performed in parallel with the tolerance and dependence study to determine the plasma drug exposure levels of the compound at the specific doses used in the tolerance and dependence study. Morphine is used as a positive control to ensure validity of the model and as a reference comparator from a similar pharmacological class.

The compound of Example 3 is evaluated at two doses, 0.3 and 3 mg/kg, administered subcutaneously four times per day. Repeated administration is found to produce peak plasma concentrations of 15 to 38 ng/mL (average, n=3) for 0.3 mg/kg dosing, and 70 to 90 ng/mL (average, n=3) for 3 mg/kg dosing. Peak concentration is reached at 30 minutes to 1.5 hours post-administration with comparable results obtained on the 1st, 14th and 28th day of administration.

At both doses of Example 3, it is found that there is no significant effect on animal body weight, food and water intake or body temperature during either the on-dose or withdrawal phase. The predominant behavioral and physical effects caused by repeated administration at 0.3 mg/kg is found to be hunched posture, Straub tail and piloerection during the dosing phase. At the higher dose, the main behavioral and physical signs observed are hunched posture, subdued behavior, Straub tail, tail rattle and piloerection.

A similar profile of behavioral and physical signs is observed following abrupt cessation of the compound on Day 28 of the study. While rearing and increased body tone were not observed during the on-dose phase for at 0.3 mg/kg, it is found to be significantly increased during the withdrawal phase. At the higher dose, mild rearing is observed during the on-dose phase, but during the withdrawal phase, rearing is more pronounced and increased body tone is observed.

As a positive control, morphine is doses at 30 mg/kg orally twice per day. This dosing regimen, as expected, is observed to be associated with changes in body weight, food and water intake, rectal temperature and clinical signs consistent with the development of tolerance and withdrawal-induced dependence. Body weight was significantly increased compared with the vehicle-treated control group on Days 2 and 3, while it was significantly decreased from Day 5. Morphine decreased food intake significantly on Days 1-9. Thereafter food intake is generally observed to be lower than for the control group, but was not significantly different from controls on Days 9, 13, 14 16, 18, 21, 22 and Day 25. These effects on body weight and food intake demonstrate tolerance to the effect of morphine.

Water intake of the morphine-treated group is also found to be significantly lower than the control group on 25 out of 28 days during the on-dose phase. Body temperature is also generally lower than the control group during the on-dose phase, significantly so on Days 20, 21 and 27. The predominant behavioral effects induced by morphine during the on-dose phase are observed to be Straub tail, jumping, digging, increased body tone, increased locomotor activity, explosive movements and exopthalmus.

Furthermore, withdrawal of morphine administration on Day 28 is observed to result in an initial further decrease in food intake followed by rebound hyperphagia, with significantly increased food intake on Day 33 versus the control group. Food intake returns to control levels by Day 35. Similarly, rats which had previously received morphine also are observed to have an initial reduction in water intake on Day 29, followed by rebound hyperdipsia (water consumption returns to control levels by Day 31). In addition, statistically significant decreases in rectal body temperature are observed during dosing, but body temperature returns to control levels during the withdrawal phase.

Moreover, new behavioral and physical signs are observed during the withdrawal phase from morphine, and this demonstrates the presence of dependence. These signs include piloerection, ataxia/rolling gait, wet dog shakes and pinched abdomen. Other abnormal behaviors observed during the on-dose phase gradually disappear during the withdrawal phase. By Day 35, rearing was the only behavior or physical sign observed with high incidence in the rats that had previously received morphine.

Thus, repeated morphine administration is shown to produce clear signs of tolerance and dependence in this study, with changes in body weight, food and water intake, rectal temperature and clinical signs consistent with the development of tolerance and withdrawal induced dependence. This demonstrates the validity of the study method in detecting physiological alterations during administration and cessation of dosing.

In contrast, repeated administration of the Compound of Example 3, at both 0.3 and 3 mg/kg four times, does not produce tolerance during subcutaneous dosing for 28 days. Furthermore, on withdrawal, a similar but decreasing profile of behavioral and physical signs is observed at the highest dose, which is not considered to be of clinical significance. Thus, overall the Compound of Example 3 was found not to produce a syndrome of physical dependence upon cessation of dosing.

Example 12: Oxycodone-Dependent Withdrawal Study in Mice

Oxycodone is administered to male C57BL/6J mice for 8 days at an increasing dose regimen of 9, 17.8, 23.7, and 33 mg/kg b.i.d. (7 hours between injections) on days 1-2, 3-4, 5-6 and 7-8 respectively. On the morning of the ninth day, the mice are administered the compound of Example 3 at either 0.3, 1 or 3 mg/kg subcutaneous. This is followed 30 minute later by either an injection of vehicle or with an injection of 3 mg/kg of naloxone. Another cohort of mice serve as negative controls, and instead of oxycodone, these mice are administered saline on days 1 to 8. On day 9, these mice are administered either vehicle (followed by naloxone, as above) or the compound of Example 3 at 3 mg/kg, s.c. (followed by naloxone, as above).

On day 9, immediately after the injection of naloxone (or vehicle), the mice are individually placed in clear, plastic cages and are observed continuously for thirty minutes. The mice are monitored for common somatic signs of opiate withdrawal, including jumping, wet dog shakes, paw tremors, backing, ptosis, and diarrhea. All such behaviors are recorded as new incidences when separated by at least one second or when interrupted by normal behavior. Animal body weights are also recorded immediately before and 30 minutes after the naloxone (or vehicle) injections. Data is analyzed with ANOVA followed by the Tukey test for multiple comparisons, when appropriate. Significant level is established at p<0.05.

The results are shown in the Table below:

Dosing: (1) on days 1-8, Total Body (2) on day 9, followed by Number Paw Weight (3) 30 minutes later of Signs Tremors Jumps Loss (1) Saline; (2) Vehicle, 2.2 0.87 0 0.5% (3) Naloxone (1) Saline; (2) Compound 5.3 0.12 0 0.4% 3.0 mg/kg, (3) Naloxone (1) Oxycodone; (2) 155.1 73.6 63.2 7.8% Compound 3.0 mg/kg, (3) Vehicle (1) Oxycodone; (2) 77.5 19.6 40.6 7.5% Compound 0.3 mg/kg, (3) Naloxone 3 mg/kg (1) Oxycodone; (2) 62.5 14.8 34.8 6.0% Compound 1.0 mg/kg, (3) Naloxone 3 mg/kg (1) Oxycodone; (2) 39.5 0.5 26.6 4.0% Compound 3.0 mg/kg, (3) Naloxone 3 mg/kg

Total number of signs includes paw tremors, jumps, and wet dog shakes. In oxycodone-treated mice, it is found that naloxone elicits a significant number of total signs, paw tremors, jumps and body weight change (p<0.0001 for each). At all doses tested, the compound of Example 3 produces a significant decrease in total number of signs and paw tremors. In addition, at 3.0 mg/kg, the compound also produces a significant decrease in jumps and attenuated body weight loss.

These results demonstrate that the compound of Example 3 dose-dependently reduces the signs and symptoms of opiate withdrawal after the sudden cessation of opiate administration in opiate-dependent rats.

Example 13: Formalin Paw Test (Inflammatory Pain Model)

Sub-plantar administration of chemical irritants, such as formalin, causes immediate pain and discomfort in mice, followed by inflammation. Subcutaneous injection of 2.5% formalin solution (37 wt % aqueous formaldehyde, diluted with saline) into the hind paw results in a biphasic response: an acute pain response and a delayed inflammatory response. This animal model thus provides information on both acute pain and sub-acute/tonic pain in the same animal.

C57 mice are first habituated in an observation chamber. 30 minutes prior to formalin challenge, mice are administered either vehicle injected subcutaneously, 5 mg/kg of morphine (in saline) injected subcutaneously, or the compound of Example 3 (in 45% w/v aqueous cyclodextrin) injected subcutaneously at either 0.3, 1.0 or 3.0 mg/kg. In addition, another set of mice are treated with the control vehicle or the compound of Example 3 at 3.0 mg/kg, via oral administration, rather than subcutaneous injection.

The mice are then given a subcutaneous injection into the plantar surface of the left hind paw of 20 μL of 2.5% formalin solution. Over the next 40 minutes, the total time spent licking or biting the treated hind-paw is recorded. The first 10 minutes represent the acute nociceptic response, while the latter 30 minutes represents the delayed inflammatory response. At one minter intervals, each animal's behavior is assessed using “Mean Behavioral Rating,” which is scored on a scale of 0 to 4:

0: no response, animal sleeping

1: animal walking lightly on treated paw, e.g., on tip-toe

2: animal lifting treated paw

3: animal shaking treated paw

4: animal licking or biting treated paw

Data are analyzed by ANOVA followed by post-hoc comparisons with Fisher tests, where appropriate. Significance is established at p<0.05.

The results are shown in the Table below.

Mean Behavior Rating Mean Licking Time (0-4) (min) 0-10 11-40 0-6 16-40 0-10 11-40 0-6 16-40 Min min min min min min min min Vehicle 1.4 1.4 2.1 1.5 34 75 32 76 (SC) Vehicle 1.2 0.9 1.9 1.0 29 50 33 40 (PO) Morphine 1.1 0.2 1.7 0.2 11 0 11 0 Cmpd, 1.5 1.0 2.3 1.2 31 68 34 70 SC 0.3 mg/kg Cmpd, 1.3 1.0 1.9 1.1 26 60 26 65 SC 1.0 mg/kg Cmpd, 0.8 0.1 1.3 0.1 14 36 11 36 SC 3.0 mg/kg Cmpd, 0.9 0.8 1.5 0.9 11 3 9 3 PO 3.0 mg/kg

The results demonstrate a significant treatment effect during both the early phase (0-10 min) and late phase (11-40 min) response periods. Post-hoc comparisons show that, compared to vehicle treatment, subcutaneous injection of morphine or the compound of Example 3 (at 3 mg/kg) significantly attenuates the pain behavior rating induced by formalin injection, as well as significantly reducing licking time. Post-hoc comparisons also show that subcutaneous injection of morphine or the compound of Example 3 (at 3 mg/kg), as well as the compound of Example 3 orally (at 3 mg/kg), significantly reduces time spent licking. While the mean pain behavior rating was also reduced using 1.0 mg/kg of compound subcutaneous and at 3.0 mg/kg oral, these effects were not statistically significant in this study. Licking time was similarly reduced using 1.0 mg/kg of the compound of Example 3 subcutaneously, but the result was not statistically significant in this study. It was also found that no mice in the study underwent significant changes in body weight in any of the study groups.

Example 14: Self Administration in Heroin-Maintained Rats

A study is performed to determine whether heroin-addicted rats self-administer the compound of Example 3, and it is found that they do not, further underscoring the non-addictive nature of the compounds of the present disclosure.

The study is performed in three stages. In the first stage, rats are first trained to press a lever for food, and they are then provided with an in-dwelling intravenous jugular catheter and trained to self-administer heroin. In response to a cue (the lighting of a light in the cage), three presses of the lever by the animal results in a single heroin injection via the catheter. The heroin is provided at an initial dose of 0.05 mg/kg/injection, and later increased to 0.015 mg/kg/injection. This trained response is then extinguished by replacing the heroin supply with saline. In the second phase, the saline solution is replaced by a solution of the compound of Example 3, at one of four doses: 0.0003 mg/kg/injection, 0.001 mg/kg/injection, 0.003 mg/kg/injection, and 0.010 mg/kg/injection. Each individual rat is provided with either one or two different doses of the compound in rising fashion. This response is then extinguished with saline injections, followed by the third phase, which repeats the use of heroin at 0.015 mg/kg/injection. The purpose of the third phase is to demonstrate that the rats still show addictive behavior to heroin at the end of the study. The study results are shown in the table below:

Animals Mean Lever Treatment (n) presses Saline Extinction 1 21 4.08 Heroin Acquisition (0.015 mg/kg/inj) 21 19.38* Cmpd. Ex. 3 at 0.0003 mg/kg/inj 8 3.17** Cmpd. Ex. 3 at 0.0003 mg/kg/inj 8 3.29** Cmpd. Ex. 3 at 0.0003 mg/kg/inj 8 3.99** Cmpd. Ex. 3 at 0.0003 mg/kg/inj 8 4.87** Saline Extinction 2 19 3.60** Heroin Reinstatement (0.015 mg/kg/inj) 19 17.08** *P < 0.001 for heroin acquisition vs. saline extinction 1 (multiple t test); **P < 0.001 for Cmpd of Ex. 3 vs. heroin acquisition (Dunnett's test); P > 0.7 for all comparisons between Cmpd. of Ex. 3 and saline extinction 1 (William's test)

The results demonstrate that there is a statistically significant increase in lever pressing by the rats when being administered heroin, but that there was no significant difference when being administered saline or the compound of Example 3. Thus, the results suggest that rats do not become addicted to the compound of Example 3.

Example 15: Animal Pharmacokinetic Data

Using standard procedures, the pharmacokinetic profile of the compound of Example 3 is studied in several animals.

Example 15a: Rat PK Studies

In a first study, rats are administered the compound of Example 2 either by intravenous bolus (IV) at 1 mg/kg in 45% Trapposol vehicle, or orally (PO) at 10 mg/kg in 0.5% CMC vehicle (N=3 each group). In a second study, rats are administered the compound of Example 2 at 10 mg/kg PO or 3 mg/kg subcutaneously (SC), each in 45% Trapposol vehicle (N=6 for each group). Plasma concentrations of the drug are measured at time points from 0 to 48 hours post dose. Representative results are tabulated below (* indicates plasma concentration below measurable level of quantitation):

Study One Study Two IV PO PO SC (1 mg/kg) (10 mg/kg) (10 mg/kg) (3 mg/kg) 30 min (ng/mL) 99.0 30.7 54.9 134.4  1 hour (ng/mL) 47.3 37.2 60.6 140.9  6 hours (ng/mL) 1.1 9.4 21.0 18.2 24 hours (ng/mL) * 0.1 0.4 1.9 48 hours(ng/mL) * * ND ND Cmax (ng/mL) 314.8 37.2 60.6 140.9 AUC (ng-hr/mL) 182 215 409 676 Bioavailability 100% 12% 22% 123% t-½ (hr) 3.1 9.5

Example 15b: Mice PK Studies

A similar study in mice is performed using 10 mg/kg PO administration of the compound of Formula 3, and the following results are obtained: Tmax=0.25 hours; Cmax=279 ng/mL; AUC (0-4 h)=759 ng-hr/mL; blood-plasma ratio (0.25-4 h) ranges from 3.7 to 6.6. The study is also conducted at a dose of 0.1 mg/kg SC. Representative results are shown in the table below:

Study: PO, 10 mg/kg SC, 0.1 mg/kg (0.5% CMC veh) (45% Trapposol veh) Plasma Brain Plasma Brain Time (hr) (ng/mL) (ng/g) (ng/mL) (ng/g) 0.25 279 1288 27.5 57.1 0.5 179 1180 31.1 71.9 1 258 989 29.2 78.5 2 153 699 14.6 38.7 4 199 734 4.7 32.6 Tmax (hr) 0.25 0.25 0.5 1.0 Cmax 279 1288 31.1 78.5 (ng/mL) AUC0-4 h 759 2491 67 191 (ng-hr/mL) B/P Ratio 3.3 2.8

Together these results show that the compounds of the present disclosure are well-absorbed and distributed to the brain and tissues and are retained with a reasonably long half-life to enable once-daily administration of therapeutic doses.

Example 16: Gastrointestinal Function

The effect of the compound of Example 3 on gastrointestinal motility in rats is examined by monitoring the rate of intestinal transit of an activated charcoal bolus. Rats were treated with either (1) aqueous carboxymethyl cellulose vehicle, (2) morphine (5 mg/kg, SC), or (3) the compound of Example 3 (at 0.3, 1.0 or 3.0 mg/kg, SC) 30 minutes prior to an oral bolus of 15% aqueous activated charcoal. The measured outcome is motility ratio, calculated as the distance traveled by the charcoal as a fraction of the full length of the animal's intestine. The results are shown in the table below:

Group (n = 10 each) Treatment Motility Ratio 1 Vehicle 0.55 2 Cmpd. Ex. 3, 0.3 mg/kg 0.50 3 Cmpd. Ex. 3, 1 mg/kg 0.55 4 Cmpd. Ex. 3, 3 mg/kg 0.50 5 Morphine, 5 mg/kg 0.27

These results show that the compound of Example 3 has no significant effect on gastrointestinal motility at a dose up to 3 mg/kg. In contrast, and as expected, morphine results in approximately a 50% reduction in gastric motility.

In a further experiment, rats were pre-treated 60 minutes prior to the charcoal bolus with either vehicle, morphine (5 mg/kg), or the compound of Example 3 (3 mg/kg), each SC, followed by treatment with either morphine (5 mg/kg), morphine plus compound of Ex. 3 (0.3 mg/kg or 3 mg/kg), or compound of Ex. 3 (3 mg/kg) alone. The results are shown in the table below. For groups 2 and 3, morphine was injected first, followed immediately by the injection of the compound of Example 3:

Group (n = Motility 8 each) Pre-Treatment Treatment Ratio 1 Vehicle Morphine, 5 mg/kg 0.21 2 None Morphine, 5 mg/kg + 0.26 Cmpd. Ex. 3, 0.3 mg/kg 3 None Morphine, 5 mg/kg + 0.32 Cmpd. Ex. 3, 3 mg/kg 4 Morphine, 5 mg/kg Cmpd. Ex. 3, 3 mg/kg 0.41 5 Cmpd. Ex. 3, 3 mg/kg Morphine, 5 mg/kg 0.30

The results show that the compound of Example 3 reverses the inhibition of gastrointestinal motility caused by morphine when given either concurrently or sequentially prior to morphine, with the blockade of morphine's effect stronger when pre-treatment is used.

Without being bound by theory, it is believed that these differences result from the compounds of the present disclosure acting as biased MOP ligands and their failure to activate beta-arrestin signaling pathways downstream, which pathways have been shown to mediate opiate-linked side effects, including constipation and respiratory depression.

Example 17: Pulmonary Function

The effect of the compound of Example 3 on pulmonary function in rats is examined by monitoring respiratory rate, tidal volume and minute volume in rats following the subcutaneous administration of the compound of Example 3 at 0.3, 1.0 and 3.0 mg/kg, compared to vehicle control. Measurements are taken at 0, 15, 60, 120, and 240 minutes following administration of the compound. It is found that there are no significant differences between the vehicle and any of the test groups at any time point. Results are shown below for 60 minutes, which is typical of the results obtained:

RR (breaths/min) TV (mL) MV (mL/min) Vehicle 188 1.10 195 Cmpd. Ex. 3, 0.3 mg/kg 181 1.06 181 Cmpd. Ex. 3, 1.0 mg/kg 203 0.86 169 Cmpd. Ex. 3, 3.0 mg/kg 190 0.97 179 

What is claimed:
 1. A method for the treatment of a central nervous system disorder, comprising administering to a patient in need thereof a compound of a Formula I:

wherein: X is —NH—; L is O; Z is —O— or —C(O)—; in free or salt form; optionally in an isolated or purified free or salt form; wherein the central nervous system disorder is (a) a pain disorder, and the patient also suffers from a gastrointestinal disorder and/or a pulmonary disorder, or (b) a pain disorder, wherein the pain disorder is traumatic pain and the patient also suffers from opioid use disorder.
 2. The method according to claim 1, wherein Z is —C(═O)—.
 3. The method according to claim 1, wherein Z is —O—.
 4. The method according to claim 1 wherein the compound is in the form of a salt.
 5. The method according to claim 1, wherein the compound is administered to the patient in the form of a pharmaceutically acceptable composition comprising the compound in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier.
 6. The method of claim 5, wherein the pharmaceutically acceptable diluent or carrier comprises a polymeric matrix.
 7. The method according to claim 6, wherein the polymeric matrix is a biodegradable poly(d,l-lactide-co-glycolide) microsphere.
 8. The method according to claim 1, wherein said patient is not responsive to or cannot tolerate the side effects from non-narcotic analgesics and/or opioid drugs, or wherein the use of opioid drugs are contraindicated in said patient.
 9. The method according to claim 8, wherein said patient is not responsive to or cannot tolerate the side effects from-opioid drugs, or wherein the use of opioid drugs are contraindicated in said patient, and said opioid drugs are selected from the group consisting of morphine, codeine, thebaine, oripavine, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl, alpha-methylfentantyl, alfentanyl, trefantinil, brifentanil, remifentanil, octfentanil, sufentanil, carfentanyl, meperidine, prodine, promedol, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol, and anileridine, or any combinations thereof.
 10. The method according to claim 1, wherein the disorder is a pain disorder and the patient also suffers from a gastrointestinal disorder and/or a pulmonary disorder.
 11. The method according to claim 10 wherein the pain disorder is selected from the group consisting of cephalic pain, idiopathic pain, neuropathic pain, chronic pain, fibromyalgia, dental pain, and traumatic pain.
 12. The method according to claim 11, wherein the pain disorder is neuropathic pain or traumatic pain.
 13. The method according to claim 10, wherein the method further comprises the administration of an additional therapeutic agent selected from the group consisting of an agonist partial agonist, inverse agonist, and antagonist, of the mu-opiate, kappa-opiate, delta-opiate, and/or nociceptin/orphanin receptors.
 14. The method according to claim 13, wherein said additional therapeutic agent is selected from the group consisting of naloxone, naltrexone, nalmefene, methadone, nalorphine, levallorphan, samidorphan, nalodeine, cyprodime, and norbinaltorphimine.
 15. The method according to claim 1, wherein the central nervous system disorder is a pain disorder, wherein the pain disorder is traumatic pain and said patient also suffers from opioid use disorder.
 16. The method according to claim 15, wherein the method further comprises administration of one or more additional therapeutic agents selected from the group consisting of an agonist, partial agonist, inverse agonist, and antagonist, of the mu-opiate, kappa-opiate, delta-opiate, and/or nociceptin/orphanin receptors.
 17. The method according to claim 16, wherein said additional therapeutic agents are selected from the group consisting of buprenorphine, methadone, naloxone, and naltrexone.
 18. The method according to claim 15, wherein the method further comprises the administration of an additional therapeutic agent selected from the group consisting of an agonist, partial agonist, inverse agonist, and antagonist, of the mu-opiate, kappa-opiate, delta-opiate, and/or nociceptin/orphanin receptors.
 19. The method according to claim 18, wherein said additional therapeutic agent is selected from the group consisting of naloxone, naltrexone, nalmefene, methadone, nalorphine, levallorphan, samidorphan, nalodeine, cyprodime, and norbinaltorphimine. 